Stable nanoparticle compositions comprising buprenorphine and at least one biodegradable polymer. The disclosure also provides methods of controlling pain in an animal and methods of treating addiction in a human utilizing the stable nanoparticle compositions, as well as pharmaceutical formulations comprising the stable nanoparticle compositions. The stable nanoparticle compositions are capable of releasing buprenorphine over several days, weeks, or months following administration. The stable nanoparticle compositions of buprenorphine utilize biodegradable polymers capable of degrading into non-toxic components in the body of an animal and may be excreted in the urine of the animal following their metabolism in the body. The stable nanoparticle compositions can advantageously provide sustained release of buprenorphine in the body after a single administration without the need for surgical removal of implanted matrices subsequent to depletion of the drug.

Buprenorphine is a semi-synthetic opiate used as an analgesic and for the treatment of addiction to heroin and other opiates. Buprenorphine is classified as a "partial agonist" with a mechanism of action similar to classical mu agonists such as morphine. Buprenorphine exerts an analgesic effect through high affinity binding to mu subclass opiate receptors in the central nervous system of animals.
Buprenorphine has a relatively short half-life of approximately two hours, and the oral absorption of buprenorphine is low as a result of a high first-pass effect in animals. Currently approved dosage forms of buprenorphine include sublingual tablets, transdermal patches, and parenteral formulations. However, the currently available formulations of buprenorphine are undesirable for a variety of reasons. For example, the sublingual tablets can be easily abused by patients and may produce psychological dependence when used chronically. Furthermore, transdermal patches require special procedures for application and disposal, and also possess a low bioavailability in patients. Finally, the currently available parenteral formulations require frequent administration via injections to the patient, sometimes as frequently as four to six injections per day.
Therefore, there exists a need for new compositions and formulations that provide sustained release of buprenorphine following administration. Moreover, new and effective methods of controlling pain and treating addiction in animals utilizing buprenorphine compositions and formulations over a prolonged period of time are also very desirable. Accordingly, the present disclosure provides stable nanoparticle compositions and formulations of buprenorphine and methods of using the compositions and formulations, which exhibit desirable properties and provide related advantages for improvement in administration and treatment of animals with buprenorphine.
The present disclosure provides stable nanoparticle compositions comprising buprenorphine and at least one biodegradable polymer. The disclosure also provides methods of controlling pain in an animal and methods of treating addiction in a human utilizing the stable nanoparticle compositions, as well as pharmaceutical formulations comprising the stable nanoparticle compositions.
The stable nanoparticle compositions, pharmaceutical formulations, and methods comprising buprenorphine according to the present disclosure provide several advantages compared to other compositions, formulations, and methods known in the art. First, the stable nanoparticle compositions are able to provide sustained or prolonged release of buprenorphine. In particular, the stable nanoparticle compositions are capable of releasing buprenorphine over, several days, weeks, or months following administration. In comparison, most currently available sustained or extended release dosage forms of buprenorphine can only release the drug over one or two days.
Second, the stable nanoparticle compositions of buprenorphine utilize biodegradable polymers capable of degrading into non-toxic components in the body of an animal and may be excreted in the urine of the animal following their metabolism in the body. Accordingly, the stable nanoparticle compositions can advantageously provide sustained release of buprenorphine in the body after a single administration without the need for surgical removal of implanted matrices subsequent to depletion of the drug.
Third, the stable nanoparticle compositions of buprenorphine can advantageously provide improved adherence of patients in need of treatment due to the lower frequency of administration. In addition, the lower frequency of administering the drug may lessen the incidence of overdose, misuse, or abuse of buprenorphine by patients.
Fourth, the stable nanoparticle compositions are capable of providing a linear releasing profile (i.e., a zero order release profile) of buprenorphine after initial rapid release. In contrast, other buprenorphine compositions such as microspheres possess a multiple phase releasing profile, which can lead to undesirable variability following administration of buprenorphine to animals. Furthermore, the releasing profile of the stable nanoparticle compositions of buprenorphine was unexpectedly consistent regardless of the drug to polymer ratio present in the nanoparticles.
Fifth, the stable nanoparticle compositions of buprenorphine possess an unexpectedly high drug to polymer ratio, high drug loading ratio, and high yield. Furthermore, the stable nanoparticle compositions of buprenorphine may possess unexpectedly greater burst effects of buprenorphine and thus could potentially be used as a loading dose in animals or for a formulation intended for a short-term release of drug.
Finally, the stable nanoparticle compositions of buprenorphine can be tailored in a formulation with a specific dose and release duration depending on the desired characteristics. In contrast, other formulations of buprenorphine purporting to provide sustained release cannot be specifically formulated to provide individualized results.
The following numbered embodiments are contemplated and are non-limiting:
1. A stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer.
2. The stable nanoparticle composition of clause 1, wherein the biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof.
3. The stable nanoparticle composition of clause 1, wherein the biodegradable polymer is PLA.
4. The stable nanoparticle composition of clause 1, wherein the biodegradable polymer is PLGA.
5. The stable nanoparticle composition of clause 1, wherein the biodegradable polymer is PCL.
6. The stable nanoparticle composition of clause 1, wherein the biodegradable polymer is PGA.
7. The stable nanoparticle composition of clause 1, wherein stable nanoparticle composition comprises more than one biodegradable polymer.
8. The stable nanoparticle composition of clause 7, wherein the stable nanoparticle composition comprises two biodegradable polymers.
9. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 1:99 to about 99:1.
10. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 5:95 to about 95:5.
11. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 10:90 to about 90:10.
12. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 15:85 to about 85:15.
13. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 20:80 to about 80:20.
14. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 25:75 to about 75:25.
15. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 30:70 to about 70:30.
16. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 35:65 to about 65:35.
17. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 40:60 to about 60:40.
18. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 45:55 to about 55:45.
19. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 10:90.
20. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 15:85.
21. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 25:75.
22. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 50:50.
23. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 75:25.
24. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 85:15.
25. The stable nanoparticle composition of clause 8, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 90:10.
26. The stable nanoparticle composition of any one of clauses 7 to 25, wherein one biodegradable polymer is PLA.
27. The stable nanoparticle composition of any one of clauses 7 to 26, wherein one biodegradable polymer is PLGA.
28. The stable nanoparticle composition of any one of clauses 7 to 27, wherein one biodegradable polymer is PCL.
29. The stable nanoparticle composition of any one of clauses 7 to 28, wherein one biodegradable polymer is PGA.
30. The stable nanoparticle composition of clause 8, wherein the first biodegradable polymer is PLA and the second biodegradable polymer is PLGA.
31. The stable nanoparticle composition of any one of clauses 1 to 30, wherein at least one biodegradable polymer is conjugated to poly(ethylene)glycol.
32. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:50.
33. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:30.
34. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:20.
35. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:10.
36. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:1.
37. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:2.
38. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:4.
39. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:5.
40. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 0.1:8.
41. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:10.
42. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:15.
43. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:16.
44. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:20.
45. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:25.
46. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:30.
47. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:32.
48. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:48.
49. The stable nanoparticle composition of any one of clauses 1 to 31, wherein the ratio of buprenorphine:polymer is about 1:50.
50. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the amount of buprenorphine is present at a range between about 0.001 to about 1000 mg.
51. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the amount of buprenorphine is present at a range between about 0.001 to about 100 mg.
52. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the amount of buprenorphine is present at a range between about 0.1 to about 100 mg.
53. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter from about 0.5 nm to about 1000 nm.
54. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter between about 10 nm to about 500 nm.
55. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter between about 100 nm to about 500 nm.
56. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter between about 200 nm to about 400 nm.
57. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter of about 100 nm.
58. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter of about 200 nm.
59. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter of about 300 nm.
60. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter of about 400 nm.
61. The stable nanoparticle composition of any one of clauses 1 to 49, wherein the stable nanoparticle composition has a diameter of about 500 nm.
62. The stable nanoparticle composition of any one of clauses 1 to 61, further comprising one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
63. The stable nanoparticle composition of any one of clauses 1 to 62, wherein the stable nanoparticle composition is lyophilized.
64. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours.
65. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours.
66. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours.
67. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours.
68. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days.
69. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days.
70. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days.
71. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days.
72. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months.
73. The stable nanoparticle composition of any one of clauses 1 to 63, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
74. The stable nanoparticle composition of any one of clauses 1 to 73, wherein the release profile of the stable nanoparticle composition is a linear release profile, optionally after initial rapid release.
75. The stable nanoparticle composition of any one of clauses 1 to 73, wherein the release profile of the stable nanoparticle composition is a non-linear release profile.
76. The stable nanoparticle composition of any one of clauses 1 to 75, wherein an agent is optionally applied to the stable nanoparticle composition.
77. The stable nanoparticle composition of clause 76, wherein the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API).
78. The stable nanoparticle composition of any one of clauses 1 to 77, wherein the stable nanoparticle composition is adapted for use as a parenteral formulation.
79. The stable nanoparticle composition of clause 78, wherein the parenteral formulation is a subcutaneous parenteral formulation.
80. The stable nanoparticle composition of clause 78, wherein the parenteral formulation is an intramuscular parenteral formulation.
81. A method of controlling pain in an animal comprising administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer.
82. The method of clause 81, wherein the pain is associated with a surgery performed or to be performed on the animal.
83. The method of clause 81, wherein the pain is acute pain.
84. The method of clause 81, wherein the pain is chronic pain.
85. The method of any one of clauses 81 to 84, wherein the animal is a human.
86. The method of any one of clauses 81 to 84, wherein the animal is an mammal.
87. The method of any one of clauses 81 to 86, wherein the biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof.
88. The method of any one of clauses 81 to 86, wherein the biodegradable polymer is PLA.
89. The method of any one of clauses 81 to 86, wherein the biodegradable polymer is PLGA.
90. The method of any one of clauses 81 to 86, wherein the biodegradable polymer is PCL.
91. The method of any one of clauses 81 to 86, wherein the biodegradable polymer is PGA.
92. The method of any one of clauses 81 to 86, wherein stable nanoparticle composition comprises more than one biodegradable polymer.
93. The method of clause 92, wherein the stable nanoparticle composition comprises two biodegradable polymers.
94. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 1:99 to about 99:1.
95. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 5:95 to about 95:5.
96. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 10:90 to about 90:10.
97. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 15:85 to about 85:15.
98. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 20:80 to about 80:20.
99. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 25:75 to about 75:25.
100. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 30:70 to about 70:30.
101. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 35:65 to about 65:35.
102. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 40:60 to about 60:40.
103. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 45:55 to about 55:45.
104. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 10:90.
105. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 15:85.
106. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 25:75.
107. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 50:50.
108. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 75:25.
109. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 85:15.
110. The method of clause 93, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 90:10.
111. The method of any one of clauses 92 to 110, wherein one biodegradable polymer is PLA.
112. The method of any one of clauses 92 to 111, wherein one biodegradable polymer is PLGA.
113. The method of any one of clauses 92 to 112, wherein one biodegradable polymer is PCL.
114. The method of any one of clauses 92 to 113, wherein one biodegradable polymer is PGA.
115. The method of clause 93, wherein the first biodegradable polymer is PLA and the second biodegradable polymer is PLGA.
116. The method of any one of clauses 81 to 115, wherein at least one biodegradable polymer is conjugated to poly(ethylene)glycol.
117. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:50.
118. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:30.
119. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:20.
120. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:10.
121. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:1.
122. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:2.
123. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:4.
124. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:5.
125. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:8.
126. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:10.
127. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:15.
128. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:16.
129. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:20.
130. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:25.
131. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:30.
132. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:32.
133. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:48.
134. The method of any one of clauses 81 to 116, wherein the ratio of buprenorphine:polymer is about 1:50.
135. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight.
136. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight.
137. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight.
138. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight.
139. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight.
101. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight.
102. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 1 mg of buprenorphine per kg of animal body weight.
103. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 2 mg of buprenorphine per kg of animal body weight.
104. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 3 mg of buprenorphine per kg of animal body weight.
105. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 4 mg of buprenorphine per kg of animal body weight.
140. The method of any one of clauses 81 to 134, wherein the stable nanoparticle composition is administered to the animal at a dose of about 5 mg of buprenorphine per kg of animal body weight.
141. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter from about 0.5 nm to about 1000 nm.
142. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter between about 10 nm to about 500 nm.
143. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter between about 100 nm to about 500 nm.
144. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter between about 200 nm to about 400 nm.
145. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter of about 100 nm.
146. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter of about 200 nm.
147. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter of about 300 nm.
148. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter of about 400 nm.
149. The method of any one of clauses 81 to 140, wherein the stable nanoparticle composition has a diameter of about 500 nm.
150. The method of any one of clauses 81 to 149, wherein the stable nanoparticle composition further comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
151. The method of any one of clauses 81 to 150, wherein the stable nanoparticle composition is lyophilized.
152. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours.
153. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours.
154. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours.
155. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours.
156. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days.
157. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days.
158. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days.
159. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days.
160. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months.
161. The method of any one of clauses 81 to 151, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
162. The method of any one of clauses 81 to 151, wherein the release profile of the stable nanoparticle composition is a linear release profile, optionally after initial rapid release.
163. The method of any one of clauses 81 to 151, wherein the release profile of the stable nanoparticle composition is a non-linear release profile.
164. The method of any one of clauses 81 to 151, wherein an agent is optionally applied to the stable nanoparticle composition.
165. The method of clause 164, wherein the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API).
166. The method of any one of clauses 81 to 165, wherein the stable nanoparticle composition is administered as a single dose.
167. The method of any one of clauses 81 to 166, wherein stable nanoparticle composition is administered as a single unit dose.
168. The method of any one of clauses 81 to 167, wherein the administration is a parenteral administration.
169. The method of clause 168, wherein the parenteral formulation is a subcutaneous parenteral formulation.
170. The method of clause 168, wherein the parenteral formulation is an intramuscular parenteral formulation.
171. A method of treating addiction in a human comprising administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer.
172. The method of clause 171, wherein the addiction is an opiate addiction.
173. The method of clause 171 or clause 172, wherein the biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof.
174. The method of clause 171 or clause 172, wherein the biodegradable polymer is PLA.
175. The method of clause 171 or clause 172, wherein the biodegradable polymer is PLGA.
176. The method of clause 171 or clause 172, wherein the biodegradable polymer is PCL.
177. The method of clause 171 or clause 172, wherein the biodegradable polymer is PGA.
178. The method of clause 171 or clause 172, wherein stable nanoparticle composition comprises more than one biodegradable polymer.
179. The method of clause 178, wherein the stable nanoparticle composition comprises two biodegradable polymers.
180. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 1:99 to about 99:1.
181. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 5:95 to about 95:5.
182. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 10:90 to about 90:10.
183. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 15:85 to about 85:15.
184. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 20:80 to about 80:20.
185. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 25:75 to about 75:25.
186. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 30:70 to about 70:30.
187. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 35:65 to about 65:35.
188. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 40:60 to about 60:40.
189. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 45:55 to about 55:45.
190. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 10:90.
191. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 15:85.
192. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 25:75.
193. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 50:50.
194. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 75:25.
195. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 85:15.
196. The method of clause 179, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 90:10.
197. The method of any one of clauses 178 to 196, wherein one biodegradable polymer is PLA.
198. The method of any one of clauses 178 to 197, wherein one biodegradable polymer is PLGA.
199. The method of any one of clauses 178 to 198, wherein one biodegradable polymer is PCL.
200. The method of any one of clauses 178 to 199, wherein one biodegradable polymer is PGA.
201. The method of clause 179, wherein the first biodegradable polymer is PLA and the second biodegradable polymer is PLGA.
202. The method of any one of clauses 171 to 201, wherein at least one biodegradable polymer is conjugated to poly(ethylene)glycol.
203. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:50.
204. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:30.
205. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:20.
206. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:10.
207. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:1.
208. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:2.
209. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:4.
210. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:5.
211. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:8.
212. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:10.
213. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:15.
214. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:16.
215. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:20.
216. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:25.
217. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:30.
218. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:32.
219. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:48.
220. The method of any one of clauses 171 to 202, wherein the ratio of buprenorphine:polymer is about 1:50.
221. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight.
222. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight.
223. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight.
224. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight.
225. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight.
226. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight.
227. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 1 mg of buprenorphine per kg of animal body weight.
228. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 2 mg of buprenorphine per kg of animal body weight.
229. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 3 mg of buprenorphine per kg of animal body weight.
230. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 4 mg of buprenorphine per kg of animal body weight.
231. The method of any one of clauses 171 to 220, wherein the stable nanoparticle composition is administered to the animal at a dose of about 5 mg of buprenorphine per kg of animal body weight.
232. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter from about 0.5 nm to about 1000 nm.
233. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter between about 10 nm to about 500 nm.
234. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter between about 100 nm to about 500 nm.
235. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter between about 200 nm to about 400 nm.
236. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter of about 100 nm.
237. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter of about 200 nm.
238. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter of about 300 nm.
239. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter of about 400 nm.
240. The method of any one of clauses 171 to 231, wherein the stable nanoparticle composition has a diameter of about 500 nm.
241. The method of any one of clauses 171 to 240, wherein the stable nanoparticle composition further comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
242. The method of any one of clauses 171 to 241, wherein the stable nanoparticle composition is lyophilized.
243. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours.
244. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours.
245. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours.
246. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours.
247. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days.
248. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days.
249. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days.
250. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days.
251. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months.
252. The method of any one of clauses 171 to 242, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
253. The method of any one of clauses 171 to 242, wherein the release profile of the stable nanoparticle composition is a linear release profile, optionally after initial rapid release.
254. The method of any one of clauses 171 to 242, wherein the release profile of the stable nanoparticle composition is a non-linear release profile.
255. The method of any one of clauses 171 to 242, wherein an agent is optionally applied to the stable nanoparticle composition.
256. The method of clause 255, wherein the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API).
257. The method of any one of clauses 171 to 256, wherein stable nanoparticle composition is administered as a single dose.
258. The method of any one of clauses 171 to 257, wherein stable nanoparticle composition is administered as a single unit dose.
259. The method of any one of clauses 171 to 258, wherein the administration is a parenteral administration.
260. The method of clause 259, wherein the parenteral formulation is a subcutaneous parenteral formulation.
261. The method of clause 259, wherein the parenteral formulation is an intramuscular parenteral formulation.
262. A pharmaceutical formulation comprising a therapeutically effective amount of a stable nanoparticle composition, wherein stable nanoparticle composition comprises buprenorphine and at least one biodegradable polymer.
263. The pharmaceutical formulation of clause 262, wherein the pharmaceutical formulation is a parenteral formulation.
264. The pharmaceutical formulation of clause 263, wherein the parenteral formulation is a subcutaneous parenteral formulation.
265. The pharmaceutical formulation of clause 263, wherein the parenteral formulation is an intramuscular parenteral formulation.
266. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight.
267. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight.
268. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight.
269. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight.
270. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight.
271. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight.
272. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 2 mg of buprenorphine per kg of animal body weight.
273. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the Pharmaceutical formulation is suitable for administration at a dose of about 3 mg of buprenorphine per kg of animal body weight.
274. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 4 mg of buprenorphine per kg of animal body weight.
275. The pharmaceutical formulation of any one of clauses 262 to 265, wherein the pharmaceutical formulation is suitable for administration at a dose of about 5 mg of buprenorphine per kg of animal body weight.
276. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least one week.
277. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least two weeks.
278. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least three weeks.
279. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least four weeks.
280. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least six weeks.
281. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least two months.
282. The pharmaceutical formulation of any one of clauses 262 to 275, wherein the pharmaceutical formulation is administered once every at least three months.
283. The pharmaceutical formulation of any one of clauses 262 to 282, wherein the biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof.
284. The pharmaceutical formulation of any one of clauses 262 to 282, wherein the biodegradable polymer is PLA.
285. The pharmaceutical formulation of any one of clauses 262 to 282, wherein the biodegradable polymer is PLGA.
286. The pharmaceutical formulation of any one of clauses 262 to 282, wherein the biodegradable polymer is PCL.
287. The pharmaceutical formulation of any one of clauses 262 to 282, wherein the biodegradable polymer is PGA.
288. The pharmaceutical formulation of any one of clauses 262 to 282, wherein stable nanoparticle composition comprises more than one biodegradable polymer.
289. The pharmaceutical formulation of clause 288, wherein the stable nanoparticle composition comprises two biodegradable polymers.
290. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 1:99 to about 99:1.
291. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 5:95 to about 95:5.
292. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 10:90 to about 90:10.
293. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 15:85 to about 85:15.
294. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 20:80 to about 80:20.
295. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 25:75 to about 75:25.
296. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 30:70 to about 70:30.
297. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 35:65 to about 65:35.
298. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 40:60 to about 60:40.
299. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 45:55 to about 55:45.
300. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 10:90.
301. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 15:85.
302. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 25:75.
303. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 50:50.
304. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 75:25.
305. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 85:15.
306. The pharmaceutical formulation of clause 289, wherein the ratio of the first biodegradable polymer to the second biodegradable polymer is about 90:10.
307. The pharmaceutical formulation of any one of clauses 288 to 306, wherein one biodegradable polymer is PLA.
308. The pharmaceutical formulation of any one of clauses 288 to 307, wherein one biodegradable polymer is PLGA.
309. The pharmaceutical formulation of any one of clauses 288 to 308, wherein one biodegradable polymer is PCL.
310. The pharmaceutical formulation of any one of clauses 288 to 309, wherein one biodegradable polymer is PGA.
311. The pharmaceutical formulation of clause 289, wherein the first biodegradable polymer is PLA and the second biodegradable polymer is PLGA.
312. The pharmaceutical formulation of any one of clauses 262 to 311, wherein at least one biodegradable polymer is conjugated to poly(ethylene)glycol.
313. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:50.
314. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:30.
315. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:20.
316. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:10.
317. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:1.
318. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:2.
319. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:4.
320. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:5.
321. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:8.
322. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:10.
323. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:15.
324. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:16.
325. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:20.
326. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:25.
327. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:30.
328. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:32.
329. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:48.
330. The pharmaceutical formulation of any one of clauses 262 to 312, wherein the ratio of buprenorphine:polymer is about 1:50.
331. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter from about 0.5 nm to about 1000 nm.
332. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter between about 10 nm to about 500 nm.
333. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter between about 100 nm to about 500 nm.
334. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter between about 200 nm to about 400 nm.
335. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter of about 100 nm.
336. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter of about 200 nm.
337. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter of about 300 nm.
338. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter of about 400 nm.
339. The pharmaceutical formulation of any one of clauses 262 to 330, wherein the stable nanoparticle composition has a diameter of about 500 nm.
340. The pharmaceutical formulation of any one of clauses 262 to 339, wherein the stable nanoparticle composition further comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
341. The pharmaceutical formulation of any one of clauses 262 to 340, wherein the stable nanoparticle composition is lyophilized.
342. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours.
343. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours.
344. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours.
345. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours.
346. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days.
347. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days.
348. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days.
349. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days.
350. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months.
351. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
352. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the release profile of the stable nanoparticle composition is a linear release profile, optionally after initial rapid release.
353. The pharmaceutical formulation of any one of clauses 262 to 341, wherein the release profile of the stable nanoparticle composition is a non-linear release profile.
354. The pharmaceutical formulation of any one of clauses 262 to 341, wherein an agent is optionally applied to the stable nanoparticle composition.
355. The pharmaceutical formulation of clause 354, wherein the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API).
356. The pharmaceutical formulation of any one of clauses 262 to 355, wherein the stable nanoparticle composition is administered as a single dose.
357. The pharmaceutical formulation of any one of clauses 262 to 356, wherein the stable nanoparticle composition is administered as a single unit dose.
358. The pharmaceutical formulation of any one of clauses 262 to 357, wherein the pharmaceutical formulation further comprises an additional active pharmaceutical agent.
359. A pharmaceutical formulation comprising a therapeutically effective amount of a stable nanoparticle composition, wherein the stable nanoparticle composition comprises a first nanoparticle component comprising buprenorphine and a first biodegradable polymer and a second nanoparticle component comprising buprenorphine and a second biodegradable polymer.
360. The pharmaceutical formulation of clause 359, wherein the stable nanoparticle composition further comprises a third nanoparticle component comprising buprenorphine and a third biodegradable polymer.
361. The pharmaceutical formulation of clause 359 or clause 360, wherein the stable nanoparticle composition further comprises a fourth nanoparticle component comprising buprenorphine and a fourth biodegradable polymer.
362. The pharmaceutical formulation of any one of clauses 359 to 361, wherein at least one biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof.
363. The pharmaceutical formulation of any one of clauses 359 to 361, wherein at least one biodegradable polymer is PLA.
364. The pharmaceutical formulation of any one of clauses 359 to 361, wherein at least one biodegradable polymer is PLGA.
365. The pharmaceutical formulation of any one of clauses 359 to 361, wherein at least one biodegradable polymer is PCL.
366. The pharmaceutical formulation of any one of clauses 359 to 361, wherein at least one biodegradable polymer is PGA.
367. The pharmaceutical formulation of any one of clauses 359 to 366, wherein the first nanoparticle component has a release profile of at least 7 days.
368. The pharmaceutical formulation of any one of clauses 359 to 366, wherein the first nanoparticle component has a release profile of at least 14 days.
369. The pharmaceutical formulation of any one of clauses 359 to 368, wherein the second nanoparticle component has a release profile of at least 7 days.
370. The pharmaceutical formulation of any one of clauses 359 to 368, wherein the second nanoparticle component has a release profile of at least 14 days.
371. The pharmaceutical formulation of any one of clauses 359 to 370, wherein the pharmaceutical formulation is a parenteral formulation.
372. The pharmaceutical formulation of clause 371, wherein the parenteral formulation is a subcutaneous parenteral formulation.
373. The pharmaceutical formulation of clause 371, wherein the parenteral formulation is an intramuscular parenteral formulation.
374. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight.
375. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose, of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight.
376. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight.
377. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight.
378. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight.
379. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight.
380. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 2 mg of buprenorphine per kg of animal body weight.
381. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 3 mg of buprenorphine per kg of animal body weight.
382. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 4 mg of buprenorphine per kg of animal body weight.
383. The pharmaceutical formulation of any one of clauses 359 to 373, wherein the pharmaceutical formulation is suitable for administration at a dose of about 5 mg of buprenorphine per kg of animal body weight.
384. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is which is administered once every at least one week.
385. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least two weeks.
386. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least three weeks.
387. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least four weeks.
388. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least six weeks.
389. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least two months.
390. The pharmaceutical formulation of any one of clauses 359 to 383, wherein the pharmaceutical formulation is administered once every at least three months.
391. The pharmaceutical formulation of any one of clauses 359 to 390, wherein at least one biodegradable polymer is conjugated to poly(ethylene)glycol.
392. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is in a range between about 10:1 to about 1:50.
393. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is in a range between about 10:1 to about 1:30.
394. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is in a range between about 10:1 to about 1:20.
395. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is in a range between about 10:1 to about 1:10.
396. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:1.
397. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:2.
398. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:4.
399. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:5.
400. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:8.
401. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:10.
402. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:15.
403. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:16.
404. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:20.
405. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:25.
406. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:30.
407. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:32.
408. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:48.
409. The pharmaceutical formulation of any one of clauses 359 to 391, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components is about 1:50.
410. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the ratio of buprenorphine:polymer in one or more nanoparticle components wherein the stable nanoparticle composition has an average diameter from about 0.5 nm to about 1000 nm.
411. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter between about 10 nm to about 500 nm.
412. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter between about 100 nm to about 500 nm.
413. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter between about 200 nm to about 400 nm.
414. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter of about 100 nm.
415. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter of about 200 nm.
416. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter of about 300 nm.
417. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter of about 400 nm.
418. The pharmaceutical formulation of any one of clauses 359 to 409, wherein the stable nanoparticle composition has an average diameter of about 500 nm.
419. The pharmaceutical formulation of any one of clauses 359 to 418, wherein one or more nanoparticle components further comprise one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
420. The pharmaceutical formulation of any one of clauses 359 to 419, wherein the stable nanoparticle composition is lyophilized.
421. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours.
422. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours.
423. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours.
424. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours.
425. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days.
426. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days.
427. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days.
428. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days.
429. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months.
430. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
431. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the release profile of the stable nanoparticle composition is a linear release profile, optionally after initial rapid release.
432. The pharmaceutical formulation of any one of clauses 359 to 420, wherein the release profile of the stable nanoparticle composition is a non-linear release profile.
433. The pharmaceutical formulation of any one of clauses 359 to 420, wherein an agent is optionally applied to the stable nanoparticle composition.
434. The pharmaceutical formulation of clause 433, wherein the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API).
435. The pharmaceutical formulation of any one of clauses 359 to 434, wherein the stable nanoparticle composition is administered as a single dose.
436. The pharmaceutical formulation of any one of clauses 359 to 435, wherein the stable nanoparticle composition is administered as a single unit dose.
437. The pharmaceutical formulation of any one of clauses 359 to 436, wherein the pharmaceutical formulation further comprises an additional active pharmaceutical agent.
Various embodiments of the invention are described herein as follows. In one embodiment described herein, a stable nanoparticle composition is provided. The stable nanoparticle composition comprises buprenorphine and at least one biodegradable polymer.
In another embodiment, a method of controlling pain in an animal is provided. The method comprises administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer.
In yet another embodiment, a method of treating addiction in a human is provided. The method comprises administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer.
In another embodiment, a pharmaceutical formulation is provided. The pharmaceutical formulation comprises a therapeutically effective amount of a stable nanoparticle composition, wherein the composition comprises buprenorphine and at least one biodegradable polymer.
In yet another embodiment, another pharmaceutical formulation is provided. The pharmaceutical formulation comprises a therapeutically effective amount of a stable nanoparticle composition, wherein the composition comprises a first nanoparticle component comprising buprenorphine and a first biodegradable polymer and a second nanoparticle component comprising buprenorphine and a second biodegradable polymer.
In the various embodiments, the stable nanoparticle composition comprises buprenorphine and at least one biodegradable polymer. The term "stable," when applied to nanoparticle compositions disclosed herein, means that the compositions maintain one or more aspects of their physical structure (e.g., size range, distribution of particles, and/or percentage of active pharmaceutical ingredient (API)) over a period of time. In some embodiments of the invention, a stable nanoparticle composition is one for which the average particle size, the maximum particle size, the range of particle sizes, and/or the distribution of particle sizes (i.e., the percentage of particles above a designated size and/or outside a designated range of sizes) is maintained for a period of time. In some embodiments, the period of time is at least about one (1) day, about one (1) week, about two (2) weeks, about one (1) month, about two (2) months, about three (3) months, about four (4) months, about five (5) months, about six (6) months, about eight (8) months, about ten (10) months, about twelve (12) months, about twenty-four (24) months, or longer. In some embodiments, the period of time is within the range of about one (1) day to about twenty-four (24) months, about two (2) weeks to about twelve (12) months, about two (2) months to about five (5) months, etc. For example, if a nanoparticle composition is subjected to prolonged storage, temperature changes, and/or pH changes and a majority of the nanoparticles in the population maintain a diameter within a stated range, the nanoparticle composition is stable. For some such populations, a majority is more than about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or more. In some embodiments, a "stable" nanoparticle composition is one for which a specified percentage of active pharmaceutical ingredient (API) remains in the nanoparticle composition. In some embodiments, the percentage of API is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or more. In one embodiment, the percentage of API is at least about 90%.
The term "nanoparticle" refers to a particle having a size measured on the nanometer scale. As used herein, the "nanoparticle" refers to a particle having a structure with a size of less than about 1,000 nanometers. As used herein, the term "nanoparticle composition" refers to any substance that contains at least one nanoparticle. In some embodiments, a nanoparticle composition is a uniform collection of nanoparticles.
In the various embodiments, the stable nanoparticle composition comprises buprenorphine. Buprenorphine is a partial g-opioid receptor agonist and is also known by chemical names such (2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol. The chemical structure of buprenorphine is:

As used herein, the term "buprenorphine" refers to buprenorphine base, pharmaceutically acceptable salts of buprenorphine, other salts of buprenorphine, metabolites of buprenorphine (e.g., norbuprenorphine), and prodrugs of buprenorphine. The term "pharmaceutically acceptable salt" refers to an addition salt that exists in conjunction with the acidic or basic portion of buprenorphine. Such salts include the pharmaceutically acceptable salts listed in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, New York, 2002 which are known to the skilled artisan. Pharmaceutically acceptable salts of an acid addition nature are formed when buprenorphine and any of its intermediates containing a basic functionality are reacted with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids commonly employed to form such acid addition salts include inorganic and organic acids. Pharmaceutically acceptable salts of a base addition nature are formed when buprenorphine and any of its intermediates containing an acidic functionality are reacted with a pharmaceutically acceptable base. Pharmaceutically acceptable bases commonly employed to form base addition salts include organic and inorganic bases.
In addition to pharmaceutically acceptable salts, other salts are included in the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically-acceptable salts, or are useful for identification, characterization or purification.
In one embodiment, buprenorphine refers to a metabolite of buprenorphine. Metabolites of buprenorphine are known in the art, for example, norbuprenorphine. In another embodiment, buprenorphine refers to a prodrug of buprenorphine. Prodrugs of buprenorphine are known in the art.
In the various embodiments, the stable nanoparticle composition comprises at least one biodegradable polymer. As used herein, the term "biodegradable" refers to a material that gradually decomposes, dissolves, hydrolyzes and/or erodes. Generally, the "biodegradable polymers" herein are polymers that are hydrolysable, and/or bioerodable in-situ primarily through hydrolysis and/or enzymolysis. The term "biodegradable polymer" as used herein is meant to include any biocompatible and/or biodegradable synthetic and natural polymers that can be used in vivo.
In some embodiments, the biodegradable polymer is selected from the group consisting of polycaprolactone (PCL), polyglycolic acid (PGA), poly(DL)-lactide (PLA), poly(DL)-lactide-co-glycolide (PLGA), or mixtures thereof. In one embodiment, the biodegradable polymer is PLA. In another embodiment, the biodegradable polymer is PLGA. In yet another embodiment, the biodegradable polymer is PCL. In one embodiment, the biodegradable polymer is PGA.
In various embodiments, the stable nanoparticle composition comprises more than one biodegradable polymer. In some embodiments, the stable nanoparticle composition comprises two biodegradable polymers. In one embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 1:99 to about 99:1. In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 5:95 to about 95:5. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 10:90 to about 90:10. In one embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 15:85 to about 85:15. In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 20:80 to about 80:20. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 25:75 to about 75:25. In one embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 30:70 to about 70:30. In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 35:65 to about 65:35. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 40:60 to about 60:40. In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is in a range between about 45:55 to about 55:45.
In one embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 10:90: In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 15:85. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 25:75. In one embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 50:50. In another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 75:25. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 85:15. In yet another embodiment, the ratio of the first biodegradable polymer to the second biodegradable polymer is about 90:10.
In various aspects, the stable nanoparticle composition comprises more than one biodegradable polymer. In one embodiment, one biodegradable polymer is PLA. In another embodiment, one biodegradable polymer is PLGA. In yet another embodiment, one biodegradable polymer is PCL. In another embodiment, one biodegradable polymer is PGA.
In other aspects, the stable nanoparticle composition comprises two biodegradable polymers. In one embodiment, the first biodegradable polymer is PLA and the second biodegradable polymer is PLGA.
In other aspects, at least one biodegradable polymer of the stable nanoparticle composition is conjugated to poly(ethylene)glycol. As used herein, the term "conjugated" refers to a complex formed between at least one nanoparticle and at least one additional agent. For example, at least one nanoparticle can be conjugated to a poly(ethylene)glycol (PEG) of varying molecular weights as known in the art. In some embodiments, the PEG may have an average molecular weight of about, e.g., 500, 1000, 2000, 3000, 3350, 3500, 4000, 4500, 5000, 6000, 8000, 10,000, or 100,000 Daltons (Da), or an average molecular weight ranging from, e.g., about 100 Da to about 100,000 Da, about 100 Da to about 6,000 Da, about 500 Da to about 5000 Da, about 1000 Da to about 4000 Da, about 2000 Da to about 4000 Da, about 2000 Da to about 6000 Da, about 1000 Da to about 10,000 Da, or about 3000 Da to about 4000 Da.
In various embodiments, the stable nanoparticle composition can have a specified ratio of buprenorphine:polymer. In one embodiment, the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:50. In another embodiment, the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:30. In yet another embodiment, the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:20. In another embodiment, the ratio of buprenorphine:polymer is in a range between about 10:1 to about 1:10.
In one embodiment, the ratio of buprenorphine:polymer is about 1:1. In another embodiment, the ratio of buprenorphine:polymer is about 1:2. In yet another embodiment, the ratio of buprenorphine:polymer is about 1:4. In one embodiment, the ratio of buprenorphine:polymer is about 1:5. In another embodiment, the ratio of buprenorphine:polymer is about 1:8. In yet another embodiment, the ratio of buprenorphine:polymer is about 1:10. In one embodiment, the ratio of buprenorphine:polymer is about 1:15. In another embodiment, the ratio of buprenorphine:polymer is about 1:16. In yet another embodiment, the ratio of buprenorphine:polymer is about 1:20. In one embodiment, the ratio of buprenorphine:polymer is about 1:25. In another embodiment, the ratio of buprenorphine:polymer is about 1:30. In yet another embodiment, the ratio of buprenorphine:polymer is about 1:32. In another embodiment, the ratio of buprenorphine:polymer is about 1:48. In yet another embodiment, the ratio of buprenorphine:polymer is about 1:50.
In various embodiments, the stable nanoparticle composition can have a specified amount of buprenorphine present in the composition. In one embodiment, the amount of buprenorphine is present at a range between about 0.001 to about 1000 mg. In another embodiment, the amount of buprenorphine is present at a range between about 0.001 to about 100 mg. In yet another embodiment, the amount of buprenorphine is present at a range between about 0.1 to about 100 mg.
In various aspects, the stable nanoparticle composition can have a specified diameter. In one embodiment, the stable nanoparticle composition has a diameter from about 0.5 nm to about 1000 nm. In another embodiment, the stable nanoparticle composition has a diameter between about 10 nm to about 500 nm. In yet another embodiment, the stable nanoparticle composition has a diameter between about 100 nm to about 500 nm. In another embodiment, the stable nanoparticle composition has a diameter between about 200 nm to about 400 nm.
In one embodiment, the stable nanoparticle composition has a diameter of about 100 nm. In another embodiment, the stable nanoparticle composition has a diameter of about 200 nm. In yet another embodiment, the stable nanoparticle composition has a diameter of about 300 nm. In another embodiment, the stable nanoparticle composition has a diameter of about 400 nm. In yet another embodiment, the stable nanoparticle composition has a diameter of about 500 nm.
In various embodiments, the stable nanoparticle composition further comprises one or more polymers. In one aspect, the stable nanoparticle composition further comprises one or more polymers selected from the group consisting of polyvinyl alcohol (PVA), PEG, sorbitan isostearate, sorbitan monopalmitate (Span 40), carboxymethylcellulose, poloxamer 188, polysorbate 20, polysorbate 80, or mixtures thereof.
In various embodiments, the stable nanoparticle composition is lyophilized. The stable nanoparticle compositions according to the present disclosure can be lyophilized to produce lyophilisates by conventional lyophilization or powders. The term "lyophilization," also known as freeze-drying, is a commonly employed technique to remove water from the preparation of interest. Lyophilization is a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. An excipient may be included in pre-lyophilized formulations to enhance stability during the freeze-drying process and/or to improve stability of the lyophilized product upon storage. For example, see Pikal, M. Biopharm. 3(9)26-30 (1990) and Arakawa et al. Pharm. Res. 8(3):285-291 (1991).
The stable nanoparticle compositions according to the present disclosure can also be dried prior to storage and/or sterilization using other methods known in the art. For example, the stable nanoparticle compositions can be air (e.g., low heat) dried, spray dried, or any other drying method known in the art. Spray drying of compositions pharmaceutical ingredients is known to those of ordinary skill in the art. For example, see Broadhead, J. et al., "The Spray Drying of Pharmaceuticals," in Drug Dev. Ind. Pharm, 18 (11 & 12), 1169-1206 (1992). Spray drying is a useful technique because it can convert a pharmaceutical preparation into a fine, dustless or agglomerated powder in a one-step process. The basic technique comprises the following four steps: a) atomization of the feed solution into a spray; b) spray-air contact; c) drying of the spray; and d) separation of the dried product from the drying air. For example, U.S. Pat. Nos. 6,235,710 and 6,001,800 describe the preparation of drug by spray drying.
In various aspects, the stable nanoparticle composition has a specified release profile. As used herein, the term "release profile" refers to the rate at which buprenorphine is released from the nanoparticle composition (e.g., the rate that the nanoparticle composition releases an amount of buprenorphine). In one embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 24 hours. In another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 48 hours. In yet another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 72 hours. In one embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 96 hours. In another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 7 days. In yet another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 14 days. In one embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 21 days. In another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 28 days. In yet another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 2 months. In another embodiment, the stable nanoparticle composition has a release profile of buprenorphine of at least 3 months.
In various aspects, the stable nanoparticle composition has a linear release profile. The term "linear release" or "linear release profile" as used herein means a constant, linear, continuous, sustained and controlled release rate of buprenorphine nanoparticle composition, i.e. the plot of drug vs. time is linear. In some embodiments, the stable nanoparticle composition has a linear release profile after initial rapid release. In other embodiments, the release profile of the stable nanoparticle composition is a non-linear release profile.
In various embodiments, an agent is optionally applied to the stable nanoparticle composition. In one aspect, the agent is selected from the group consisting of a surfactant, a stabilizer, a biomarker for targeting, or a second active pharmaceutical ingredient (API). The term "surfactant," as used herein, is to be interpreted broadly to relate to any composition that is capable of altering "surface tension between a liquid and any precipitated particles suspended in the liquid. Suitable surfactants are taught in McCutcheon's Emulsifiers & Detergents, at pages 287-310 of the North American Edition (1994), and in McCutcheon's Emulsifiers & Detergents, at pages 257-278 and 280 of the International Edition (1994), both published by MC Publishing Co. (McCutcheon Division) of Glen Rock, N.J.
As used herein, the term "stabilizer" refers to any chemical, compound, or material that minimizes the degradation of buprenorphine or biodegradable polymer in the nanoparticle compositions. Examples of stabilizers include, but are not limited to, aluminum salts, bicarbonate salts of aluminum, Group IA metals or Group IIA metal salts (such as, but not limited to, sodium salts, calcium salts, magnesium salts, etc.), bicarbonate salts of Group IA or Group IIA salts (such as a bicarbonate salt of sodium, a bicarbonate salt of magnesium, a bicarbonate salt of calcium), polymers, sodium alginate, sterols, fatty alcohols and combinations thereof. Examples of polymers that can be used as stabilizers include, but are not limited to, semipermeable homopolymers, semipermeable copolymers, and the like.
As used herein, a "biomarker" for targeting includes any such biomarkers known in the art to be capable of targeting cells and/or disease processes. For example, a biomarker of a disease or condition refers to a gene or a gene product that is up- or down-regulated in a biological sample of a subject having the disease or condition relative to a biological sample from like tissue derivation, which gene or gene product is sufficiently specific to the disease or condition that it can be used, optionally with other genes or gene products, to identify or detect the disease or condition.
In various embodiments, stable nanoparticle composition is adapted for use as a parenteral formulation. The term "parenteral formulation" refers to a formulation suitable for the administration of the stable nanoparticle composition via injection under or through one or more layers of skin or mucus membranes of an animal, such as a human. Standard parenteral injections are given into the intradermal, subcutaneous, or intramuscular region of an animal. In some embodiments, a deep location is targeted for injection of the stable nanoparticle compositions as described herein. In one embodiment, the parenteral formulation is a subcutaneous parenteral formulation. In another embodiment, the parenteral formulation is an intramuscular parenteral formulation.
In another aspect of the present disclosure, a method of controlling pain in an animal is provided. The method comprises administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer. The previously described embodiments of the stable nanoparticle composition are applicable to the method of controlling pain in an animal described herein.
As used herein, the terms "control of pain" or "controlling pain" refer to preventing, minimizing, or eliminating pain in an animal. As used herein, the term "pain" represents all categories of pain, including traumatic pain resulting from tissue injury, post-surgical pain, burn pain, inflammatory pain, pain associated with disease (such as cancer, infection, osteoarthritis, rheumatoid arthritis, or other type of arthritis), pain associated with nerve damage, neuropathy, and other forms of neuralgic, neuropathic and idiopathic pain syndromes, and specific organ or tissue pain, such as ocular and corneal pain, bone pain, heart pain, skin pain, visceral (kidney, gall bladder, gastrointestinal, etc.) pain, joint pain, dental pain, and muscle pain. The term "pain" also includes pain of varying severity, i.e. mild, moderate and severe pain, as well as acute and chronic pain.
In various embodiments of the method, the pain is associated with a surgery performed or to be performed on the animal. In another embodiment, the pain is acute pain. The term "acute pain" refers to pain resulting from an acute event and generally decreasing in intensity over a period of a few days to a few weeks. In yet another embodiment, the pain is chronic pain. The term "chronic pain" refers to pain resulting from an acute or repeated events and generally increasing in intensity over a period of a few weeks to years.
As used herein, the term "animal" refers to a mammal, for example, a human or a non-human mammal, e.g., a primate, dog, cat, bovine, ovine, porcine, equine, mouse, rat, hamster, rabbit, or guinea pig. The terms "patient," "subject," or "individual" can be used interchangeably to refer to an animal. In one embodiment, the animal is a human. In another embodiment, the animal is an equine.
In carrying out the methods of this disclosure, the amount of buprenorphine in the stable nanoparticle composition is adequate to achieve a therapeutic effect. As used herein, the term "therapeutically effective amount" refers to an amount which gives the desired benefit to an animal and includes both treatment and prophylactic administration. The amount will vary from one animal to another and will depend upon a number of factors, including the overall physical condition of the animal and the underlying cause of the condition to be treated.
The amount of buprenorphine used for the controlling pain gives an acceptable rate of change and maintains desired response at a beneficial level. A therapeutically effective amount of the composition used in the methods of the present disclosure may be readily ascertained by one of ordinary skill in the art using publicly available materials and procedures. In one embodiment of the present invention, the therapeutically effective amount of buprenorphine to be delivered can be quantified by determining milligrams of buprenorphine per kilogram of animal body weight.
In various aspects of the method, the therapeutically effective amount is an amount sufficient to achieve a minimum effective plasma concentration (MEC). Generally, MEC has been defined as the minimum plasma concentration of an analgesic that is sufficient to prevent a patient from requesting a supplementary analgesic. The MEC of buprenorphine is well known to the skilled artisan.
In some embodiments of the method, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight. In one embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight. In another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight. In one embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight. In another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight.
In one embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 1 mg of buprenorphine per kg of animal body weight. In another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 2 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 3 mg of buprenorphine per kg of animal body weight. In another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 4 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition is administered to the animal at a dose of about 5 mg of buprenorphine per kg of animal body weight.
In various aspects of the method, the stable nanoparticle composition is administered as a single dose. In other aspects of the method, the stable nanoparticle composition is administered as a single unit dose. As used herein, the term "unit dose" is a discrete amount of the composition comprising a predetermined amount of buprenorphine. The amount of buprenorphine is generally equal to the dosage of buprenorphine which would be administered to an animal or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
According to the methods of the present disclosure, the terms "single dose" and "single unit dose" include embodiments wherein the composition can be administered as a single parenteral injection or administered as multiple parenteral injections. In one embodiment, a single dose or single unit dose of the composition can be parenterally administered to an animal at one location on the animal's body. In another embodiment, a single dose or single unit dose of the composition can be parenterally administered to an animal in multiple injections at a single location on the animal's body. In yet another embodiment, a single dose or single unit dose of the composition can be parenterally administered to an animal in multiple injections at more than one location on the animal's body. In embodiments wherein multiple injections of the composition are utilized, the multiple injections can be administered to the animal over a reasonable duration of time.
In another aspect of the present disclosure, a method of treating addiction in a human is provided. The method comprises administering to the animal in need thereof a therapeutically effective amount of a stable nanoparticle composition comprising buprenorphine and at least one biodegradable polymer. The previously described embodiments of the stable nanoparticle composition are applicable to the method of treating addiction in a human described herein. The previously described embodiments of the method of controlling pain in an animal, with respect to animals, the amount of buprenorphine in the stable nanoparticle composition is adequate to achieve a therapeutic effect, the therapeutically effective amount of buprenorphine in the stable nanoparticle composition administered to the animal, single doses, and single unit doses are also applicable to the method of treating addiction in a human.
As used herein, the term "addiction" broadly encompasses the process whereby physical and/or psychological dependence develops to a drug. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Drug addiction is considered a pathological state. The disorder of addiction involves the progression of acute drug use to the development of drug-seeking behavior, the vulnerability to relapse, and the decreased, slowed ability to respond to naturally rewarding stimuli. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has categorized three stages of addiction: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. These stages are characterized, respectively, by constant cravings and preoccupation with obtaining the substance; using more of the substance than necessary to experience the intoxicating effects; and experiencing tolerance, withdrawal symptoms, and decreased motivation for normal life activities. The term "drug addiction" as used herein is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include: (i) an overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means; (ii) a tendency to increase the dose; (iii) a psychic (psychological) and generally a physical dependence on the effects of the drug; and (iv) detrimental effects on the individual and on society. In one embodiment, the addiction is an opiate addiction.
In another aspect of the present disclosure, a pharmaceutical formulation is provided. The pharmaceutical formulation comprises a therapeutically effective amount of a stable nanoparticle composition, wherein the composition comprises buprenorphine and at least one biodegradable polymer. The previously described embodiments of the stable nanoparticle composition are applicable to the pharmaceutical formulation.
In various embodiments, the pharmaceutical formulation is suitable for administration at a specified dose range. In one embodiment, pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 1000 mg of buprenorphine per kg of animal body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 100 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.01 to about 100 mg of buprenorphine per kg of animal body weight. In one embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 100 mg of buprenorphine per kg of animal body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 10 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 1 to about 5 mg of buprenorphine per kg of animal body weight. In one embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 2 mg of buprenorphine per kg of animal body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 3 mg of buprenorphine per kg of animal body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 4 mg of buprenorphine per kg of animal body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 5 mg of buprenorphine per kg of animal body weight.
In various aspects, the pharmaceutical formulation is administered at specified time intervals. In one embodiment, the pharmaceutical formulation is administered once every at least one week. In another embodiment, the pharmaceutical formulation is administered once every at least two weeks. In yet another embodiment, the pharmaceutical formulation is administered once every at least three weeks. In one embodiment, the pharmaceutical formulation is administered once every at least four weeks. In another embodiment, the pharmaceutical formulation is administered once every at least six weeks. In yet another embodiment, the pharmaceutical formulation is administered once every at least two months. In another embodiment, the pharmaceutical formulation is administered once every at least three months.
In other embodiments, the pharmaceutical formulation further comprises an additional active pharmaceutical agent.
In another aspect of the present disclosure, a second pharmaceutical formulation is provided. The pharmaceutical formulation comprises a therapeutically effective amount of a stable nanoparticle composition, wherein the composition comprises a first nanoparticle component comprising buprenorphine and a first biodegradable polymer and a second nanoparticle component comprising buprenorphine and a second biodegradable polymer. The previously described embodiments of the first described pharmaceutical formulation are applicable to the second pharmaceutical formulation.
In some embodiments of this pharmaceutical formulation, the stable nanoparticle composition further comprises a third nanoparticle component comprising buprenorphine and a third biodegradable polymer. In other embodiments of this pharmaceutical formulation, the stable nanoparticle composition further comprises a fourth nanoparticle component comprising buprenorphine and a fourth biodegradable polymer.
In various embodiments of this pharmaceutical formulation, the first nanoparticle component of the pharmaceutical formulation has a release profile of at least 7 days. In other embodiments of this pharmaceutical formulation, the first nanoparticle component has a release profile of at least 14 days. In yet other embodiments of this pharmaceutical formulation, the second nanoparticle component has a release profile of at least 7 days. In still other embodiments of this pharmaceutical formulation, the second nanoparticle component has a release profile of at least 14 days.

Buprenorphine nanoparticle composition and methods thereof