A pharmaceutical composition containing macrolide, e.g. a rapamycin compound in an emulsion preconcentrate or microemulsion preconcentrate for oral administration. The carrier medium for the rapamycin compound includes a hydrophilic phase, a lipophilic phase and a surfactant. The composition is stable and provides high absorption efficiency.

This invention relates to galenic formulations containing macrolides, e.g. compounds of the rapamycin class. In particular this invention relates to galenic formulations which are in the form of micro-emulsions, micro-emulsion preconcentrates, emulsion or emulsion-preconcentrate.
The macrolide may contain e.g. 1, 2 or 3 ring oxygen or nitrogen or other atoms besides carbon atoms. It may have side chains, e.g. in the form of fused rings, or substituents,e.g. oxy groups. It may contain double bonds. It may contain e.g. from 15 to 35 ring atoms e.g. of carbon.
Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. It has been found to be pharmaceutically useful in a variety of applications, particularly as an immunosuppressant for use in the treatment and prevention of organ transplant rejection and autoimmune diseases. Rapamycin has the following structure:
(Kesseler, H., et al., Helv. Chim. Acta (1993) 76: 117; U.S. Pat. No. 3,929,992). Large numbers of derivatives of rapamycin have been synthesized, including for example those disclosed in U.S. Pat. Nos. 5,221,670 and 5,221,740, certain acyl and aminoacyl-rapamycins (see for example U.S. Pat. No. 4,316,885, U.S. Pat. No. 4,650,803, and U.S. Pat. No. 5,151,413), and carbonates and amide esters (see for example EP 509795 and 515140) 27-desmethyl-rapamycin (see for example WO 92/14737), 26-dihydro-rapamycin (see for example U.S. Pat. No. 5,138,051), alkoxyester derivatives (see for example U.S. Pat. No. 5,233,036), and certain pyrazole derivatives (U.S. Pat. No. 5,164,399).
Rapamycin and its structurally similar analogs and derivatives are termed collectively as xe2x80x9ccompounds of the rapamycin classxe2x80x9d in this specification.
Compounds of the rapamycin class are extremely potent immunosuppressants and have also been shown to have antitumor and antifungal activity. However their utility as pharmaceuticals especially on oral administration has been restricted by their very low solubility, low and variable bioavailability and their high toxicity. Little is known concerning the causes of these properties and the site of absorption. Thus low bioavailability may be thought to due to due to extensive metabolism of the macrolide ring and not solvable by a galenical formulation. Therefore there is a need for an acceptable pharmaceutical composition that contains compounds of the rapamycin class.
FK506 is a macrolide immunosuppressant that is produced by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in the appendix to the Merck Index, as item A5. Also a large number of related compounds which retrain the basic structure and immunological properties of FK506 are also known. These compounds are described in a large number of publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, WO 93/5059 and the like. Little is known concerning the biopharmaceutical properties of such compounds. These compounds are termed collectively xe2x80x9cFK506 compoundsxe2x80x9d in this specification.
It has now been surprisingly found that stable compositions containing macrolides that offer high absorption efficiency, can be obtained by formulating the macrolide with certain carrier media.
Accordingly, this invention provides a pharmaceutical composition comprising a macrolide and a carrier medium comprising a hydrophilic phase, a lipophilic phase and a surfactant.
In another aspect the invention provides a pharmaceutical composition which comprises an orally administrable active agent which is other than a cyclosporin and a microemulsion preconcentrate carrier medium therefor which comprises
i) a reaction product of castor oil and ethylene oxide,
ii) a transesterification product of a vegetable oil and glycerol comprising predominantly linoleic acid or oleic acid mono-, di- and tri-glycerides, or a polyoxyalkylated vegetable oil,
iii) 1,2 propylene glycol and
iv) ethanol.
The pharmaceutical composition is stable and results in surprisingly high and consistent absorption efficiency when administered orally. Therefore the macrolide may be administered in lower doses, which alleviates toxicity problems. For example, in animal trials in which the pharmaceutical compositions are administered orally, the pharmaceutical compositions resulted in high bioavailabilities. Hence the pharmaceutical compositions have very surprising properties which offer great advantages.
Preferably the composition is in the form of a xe2x80x9cmicroemulsion preconcentratexe2x80x9d or xe2x80x9cemulsion preconcentratexe2x80x9d, in particular of the type providing o/w (oil-in-water) microemulsions or emulsions. However the composition may be in the form of a microemulsion or an emulsion which additionally contains an aqueous phase; preferably water.
A xe2x80x9cmicroemulsion preconcentratexe2x80x9d is defined in this specification as being a formulation which spontaneously forms a microemulsion in an aqueous medium, for example, in water or in the gastric juices after oral application.
A xe2x80x9cmicroemulsionxe2x80x9d is a non-opaque or substantially non-opaque colloidal dispersion that is formed spontaneously or substantially spontaneously when its components are brought into contact. A microemulsion is thermodynamically stable and contains dispersed particles of a size less than about 2000 xc3x85. Generally microemulsions comprise droplets or particles having a diameter of less than about 1500 xc3x85; typically from 30 to 1000 xc3x85. Further characteristic can be found in British patent application 2 222 770 A; the disclosure of which is incorporated herein by reference.
An xe2x80x9cemulsion preconcentratexe2x80x9d is defined in this specification as being as being a formulation which spontaneously forms an emulsion in an aqueous medium, for example, in water or in the gastric juices after oral application. The emulsion formed is opaque, thermodynamically stable and contains dispersed droplets of a size greater than about 100 nm, more usually greater than about 200 nm. Often bimodal size range distributions are obtained. The emulsion preconcentrates are preferably of the type providing o/w (oil-in-water) emulsions.
A xe2x80x9cpharmaceutical compositionxe2x80x9d means a composition in which the individual components or ingredients are themselves pharmaceutically acceptable and, when a particular form of administration is foreseen, are suitable or acceptable for that form of administration.
The lipophilic phase may comprise 10 to 85% by weight of the carrier medium; preferably 15 to 70% by weight, more preferably 20 to 60% by weight and even more preferably about 25% by weight.
The surfactant may comprise 5 to 80% by weight of the carrier medium; preferably 10 to 70% by weight, more preferably 20 to 60% by weight and even more preferably about 40% by weight.
The hydrophilic phase may comprise 10 to 50% by weight of the carrier medium; preferably 15 to 40% by weight, more preferably 20 to 35% by weight and even more preferably about 30% by weight.
The macrolide is preferably present in an amount of 1 to 15% by weight of the composition; more preferably about 2 to 10%.
The macrolide may be rapamycin or an O-substituted derivative in which the hydroxy in position 40 of the formula illustrated above is replaced by xe2x80x94OR1 in which R1 is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and aminoalkyl; for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)-rapamycin. These O-substituted derivatives may be produced by reacting Rapamycin (or dihydro or deoxorapamycin) with an organic radical attached to a leaving group (for example RX where R is the organic radical which is desired as the O-substituent, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CCl3C(NH)O or CF3SO3) under suitable reaction conditions. The conditions may be acidic or neutral conditions, for example in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CCl3C(NH)O or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF3SO3.
A preferred compound is 40-O-(2-hydroxy)ethyl rapamycin (hereinafter compound A) as disclosed in PCT/EP/93/02604.
Examples of compounds of the FK 506 class are those mentioned above. They include for example FK 506, ascomycin and other naturally occuring compounds. They include also synthetic analogues.
A preferred compound of the FK 506 class is disclosed in EP 427 680, e.g. Example 66a. Other preferred compounds are disclosed in EP 465 426.
The hydrophilic phase may be selected from Transcutol (which has the formula C2H5xe2x80x94[Oxe2x80x94(CH2)2]2xe2x80x94OH), Glycofurol (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether) and 1,2-propylene glycol, or mixtures thereof, and is preferably 1,2-propylene glycol. The hydrophilic phase may include further hydrophilic co-components, for example lower alkanols such as ethanol. These co-components will generally be present in partial replacement of other components of the hydrophilic phase. While the use of ethanol in the compositions is not essential, it has been found to be of particular advantage when the compositions are to be manufactured in soft gelatine, encapsulated form. This is because storage characteristics are improved, in particular the risk of rapamycin precipitation following encapsulation procedures is reduced. Thus the shelf life stability may be extended by employing ethanol or some other such co-component as an additional ingredient of the hydrophilic phase. The ethanol may comprise 0 to 60% by weight of the hydrophilic phase; preferably 20 to 55% by weight and more preferably about 40 to 50% by weight. Small quantities of liquid polyethylene glycols may also be included in the hydrophilic phase.
Preferred lipophilic phase components are medium chain fatty acid triglycerides, mixed mono-, di-, tri-glycerides, and transesterified ethoxylated vegetable oils.
Suitable medium chain fatty acid triglycerides are those known and commercially available under the trade names Miglyol, Captex, Myritol, Capmul, Captex, Neobee and Mazol; Miglyol 812 being the most preferred. These triglycerides are described in Fiedler, H. P. xe2x80x9cLexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebietexe2x80x9d, Editio Cantor, D-7960 Aulendorf, 3rd revised and expanded edition (1989), the contents of which are hereby incorporated by reference.
The mixed mono-, di-, tri-glycerides preferably comprise mixtures of C12-20 fatty acid mono-, di- and tri-glycerides, especially mixed C16-18 fatty acid mono-, di- and triglycerides. The fatty acid component of the mixed mono-, di- and tri-glycerides may comprise both saturated and unsaturated fatty acid residues. Preferably however they are predominantly comprised of unsaturated fatty acid residues; in particular C18 unsaturated fatty acid residues. Suitably the mixed mono-, di-, tri-glycerides comprise at least 60%, preferably at least 75%, more preferably at least 85% by weight of a C18 unsaturated fatty acid (for example linolenic, linoleic and oleic acid) mono-, di- and tri-glycerides. Suitably the mixed mono-, di-, tri-glycerides comprise less than 20%, for example about 15% or 10% by weight or less, saturated fatty acid (for example palmitic and stearic acid) mono-, di- and tri-glycerides.
The mixed mono-, di-, tri-glycerides are preferably predominantly comprised of mono- and di-glycerides; for example mono- and di-glycerides comprise at least 50%, more preferably at least 70% based on the total weight of the lipophilic phase. More preferably, the mono- and di-glycerides comprise at least 75% (for example about 80% or 85% by weight of the lipophilic phase.
Preferably the monoglycerides comprise from about 25 to about 50%, based on the total weight of the lipophilic phase, of the mixed mono-, di-, tri-glycerides. More preferably from about 30 to about 40% (for example 35 to 40%) monoglycerides are present.
Preferably the diglycerides comprise from about 30 to about 60%, based on the total weight of the lipophilic phase, of the mixed mono-, di-, tri-glycerides. More preferably from about 40 to about 55% (for example 48 to 50%) diglycerides are present.
The triglycerides suitably comprise at least 5% but less than about 25%, based on the total weight of the lipophilic phase, of the mixed mono-, di-, tri-glycerides. More preferably from about 7.5 to about 15% (for example from about 9 to 12%) triglycerides are present.
The mixed mono-, di-, tri-glycerides may be prepared by admixture of individual mono-, di- or tri-glycerides in appropriate relative proportion. Conveniently however they comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil or, preferably, corn oil, sunflower oil or safflower oil and most preferably corn oil, with glycerol.
Such transesterification products are generally obtained by heating the selected vegetable oil with glycerol, at high temperature in the presence of an appropriate catalyst under an inert atmosphere with continuous agitation (for example in a stainless steel reactor) to effect trans-esterification or glycerolysis. In addition to their mono-, di- and tri-glyceride components, the transesterification products also generally comprise minor amounts of free glycerol. The amount of free glycerol present is preferably less than 10%, more preferably less than 5%, most preferably about 1 or 2% by weight based on the total weight of free glycerol plus mono-, di- and tri-glycerides.
Preferably some of the glycerol is first removed to give a xe2x80x9csubstantially glycerol free batchxe2x80x9d when soft gelatine capsules are to be made.
Trans-esterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides. An example of a suitable mixed glyceride product is the trans-esterification product commercially available under the trade name MAISINE. This product is comprised predominantly of linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself being comprised of about 56% by weight linoleic acid, 30% oleic acid, about 10% palmitic and about 3% stearic acid constituents). The physical characteristics of MAISINE [available from the company Etablissements Gattefossxc3xa9, of 36, Chemin de Genas, P.O.Box 603, 69804 Saint-Priest, Cedex (France)] are: up to 10% (typically 3.9 to 4.9% or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 0.2%) free glycerol; about 35% (typically 30 to 40% or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 32 to 36%, for example about 36%) mono-glycerides; about 50% (or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches about 46 to 48%) di-glycerides; about 10% (or, in xe2x80x9csubstantially glycerol freexe2x80x9d batches, about 12 to 15%) tri-glycerides; and about 1% free oleic acid.
Further physical characteristics for MAISINE are: an acid value of maximum about 2, an iodine no. of about 85 to 105, a saponification no. of about 150 to 175 (Fiedler xe2x80x9cLexikon der Hilfsstoffexe2x80x9d, 3rd revised and expanded edition (1989) Vol. 2, p.768). The fatty acid content for MAISINE is typically: about 11% palmitic acid; about 2.5% stearic acid; about 29% oleic acid; about 56% linoleic acid; and 1.5% other acids.
It is especially preferred that the mixed mono-, di-, and tri-glycerides are clear and remain clear for more than 20 days upon storage at temperatures of 20xc2x0 C. to 25xc2x0 C. Also, a sample of the mixed mono-, di-, and tri-glycerides, which has been kept in a refrigerator at about between 2 and 8xc2x0 C. for 24 hours and then held at room temperature for 1 hour, should be clear.
Preferably the mono-, di-, tri-glycerides have a low saturated fatty acid content. Mixed mono-, di-, tri-glycerides meeting these requirements may be obtained from commercially available products by separation techniques as known in the art (for example freezing procedures coupled with separation techniques such as centrifugation) to remove the saturated fatty acid components and enhance the unsaturated fatty acid component content. Typically the total saturated fatty acid component content will be less than 15%, (for example  less than 10%, or  less than 5%) by weight based on the total weight of the lipophilic phase. A reduction of the content of saturated fatty acid component in the mono-glyceride fraction may be observed after being subjected to the separation technique. A suitable process is described in WO 93/09211.
The mixed mono-, di-, tri-glycerides thus preferably contain lesser quantities of saturated fatty acids (e.g. palmitic and stearic acids) and relatively greater quantities of unsaturated fatty acids (e.g. oleic and linoleic acids) than the starting material.
A suitable example of a mixed mono-, di-, tri-glyceride product containing lesser quantities of saturated fatty acids contains: 32 to 36% mono-glycerides, 45 to 55% di-glycerides and 12 to 20% tri-glycerides, by weight based on the total weight of the lipophilic phase. Further characteristics include the following:
Mixed mono-, di-, tri-glycerides complying with these characteristics are referred to in this specification as xe2x80x9crefined glycerol-transesterified corn oilsxe2x80x9d. The xe2x80x9crefined glycerol-transesterified corn oilsxe2x80x9d have the advantage of remaining stable for a long time.
The lipophilic phase may alternatively comprise suitable transesterified ethoxylated vegetable oils such as those obtained by reacting various natural vegetable oils (for example, maize oil, kernel oil, almond oil, ground nut oil, olive oil, soybean oil, sunflower oil, safflower oil and palm oil, or mixtures thereof) with polyethylene glycols that have an average molecular weight of from 200 to 800, in the presence of an appropriate catalyst. These procedures are known and an example is described in U.S. Pat. No. 3,288,824. Transesterified ethoxylated corn oil is particularly preferred.
Transesterified ethoxylated vegetable oils are known and are commercially available under the trade name LABRAFIL (H. Fiedler, loc cit, vol 2, page 707). Examples are LABRAFIL M 2125 CS (obtained from corn oil and having an acid number of less than about 2, a saponification number of 155 to 175, an HLB value of 3 to 4, and an iodine number of 90 to 110), and LABRAFIL M 1944 CS (obtained from kernel oil and having an acid number of about 2, a saponification number of 145 to 175 and an iodine number of 60 to 90). LABRAFIL M 2130 CS (which is a transesterification product of a C12-18 glyceride and polyethylene glycol and which has a melting point of about 35 to 40xc2x0 C., an acid number of less than about 2, a saponification number of 185 to 200 and an iodine number of less than about 3) may also be used. The preferred transesterified ethoxylated vegetable oil is LABRAFIL M 2125 CS which can be obtained, for example, from Gattefossxc3xa9, Saint-Priest Cedex, France.
Examples of suitable surfactants are:
i) reaction products of a natural or hydrogenated castor oil and ethylene oxide. The natural or hydrogenated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1:35 to about 1:60, with optional removal of the polyethyleneglycol component from the products. Various such surfactants are commercially available. The polyethyleneglycol-hydrogenated castor oils available under the trade name CREMOPHOR are especially suitable. Particularly suitable are CREMOPHOR RH 40, which has a saponification number of about 50 to 60, an acid number less than about 1, a water content (Fischer) less than about 2%, an nD60 of about 1.453 to 1.457 and an HLB of about 14 to 16; and CREMOPHOR RH 60, which has a saponification number of about 40 to 50, an acid number less than about 1, an iodine number of less than about 1, a water content (Fischer) of about 4.5 to 5.5%, an nD25 of about 1.453 to 1.457 and an HLB of about 15 to 17. An especially preferred product of this class is CREMOPHOR RH40. Also suitable are polyethyleneglycol castor oils such as that available under the trade name CREMOPHOR EL, which has a molecular weight (by steam osmometry) of about 1630, a saponification number of about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32 and an nD25 of about 1.471. Similar or identical products which may also be used are available under the trade names NIKKOL (e.g. NIKKOL HCO-40 and HCO-60), MAPEG (e.g. MAPEG CO-40h), INCROCAS (e.g. INCROCAS 40), and TAGAT (e.g. TAGAT RH 40). These surfactants are further described in Fiedler loc. cit.
ii) Polyoxyethylene-sorbitan-fatty acid esters, for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the type known and commercially available under the trade name TWEEN (Fiedler, loc. cit. p.1300-1304) including the products TWEEN
20 [polyoxyethylene(20)sorbitanmonolaurate],
21 [polyoxyethylene(4)sorbitanmonolaurate],
40 [polyoxyethylene(20)sorbitanmonopalmitate],
60 [polyoxyethylene(20)sorbitanmonostearate],
65 [polyoxyethylene(20)sorbitantristearate],
80 [polyoxyethylene(20)sorbitanmonooleate],
81 [polyoxyethylene(5)sorbitanmonooleate],
85 [polyoxyethylene(20)sorbitantrioleate].
Especially preferred products of this class are TWEEN 40 and TWEEN 80.
iii) Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type known and commercially available under the trade name MYRJ (Fiedler, loc. cit., 2, p.834-835). An especially preferred product of this class is MYRJ 52 having a D25 of about 1.1., a melting point of about 40 to 44xc2x0 C., an HLB value of about 16.9., an acid value of about 0 to 1 and a saponification no. of about 25 to 35.
iv) Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, for example of the type known and commercially available under the trade names PLURONIC, EMKALYX and POLOXAMER (Fiedler, loc. cit., 2, p. 959). An especially preferred product of this class is PLURONIC F68, having a melting point of about 52xc2x0 C. and a molecular weight of about 6800 to 8975. A further preferred product of this class is POLOXAMER 188.
v) Dioctylsulfosuccinate or di-[2-ethylhexyl]-succinate (Fiedler, loc. cit., 1, p. 107-108).
vi) Phospholipids, in particular lecithins (Fiedler, loc. cit., 2, p. 943-944). Suitable lecithins include, in particular, soya bean lecithins.
vii) Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the trade name MIGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth (Fiedler, loc. cit., 2, p. 808-809).
It will also be appreciated that the components of the carrier medium may contain unreacted starting materials, e.g. polyethylene glycol.
The surfactant selected preferably has an HLB of at least 10.
Preferably the relative proportion of hydrophilic phase component(s), the lipophilic phase and the surfactant lie within the xe2x80x9cmicroemulsionxe2x80x9d region on a standard three way plot. The compositions thus obtained are microemulsion preconcentrates of high stability that are capable, on addition to water, of providing microemulsions having an average particle size of  less than 1.500 xc3x85 and stable over periods in excess of 24 hours.
The microemulsion preconcentrate compositions show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to three years, and even longer.
Alternatively the components may be selected to provide an emulsion preconcentrate. The emulsion preconcentrate compositions also show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to three years, and even longer.
The pharmaceutical composition may also include further additives or ingredients, for example antioxidants (such as ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols) and/or preserving agents. These additives or ingredients may comprise about 0.05 to 1% by weight of the total weight of the composition. The pharmaceutical composition may also include sweetening or flavoring agents in an amount of up to about 2.5 or 5% by weight based on the total weight of the composition. Preferably the antioxidant is xcex1-tocopherol (vitamin E).
The pharmaceutical composition may also include one or more other immunosuppressants such as, for example, a cyclosporin or if a rapamycin is present a FK 506 compound as described above. Cyclosporins comprise a class of cyclic, poly-N-methylated undecapeptides, generally possessing immunosuppressive, anti-inflammatory, anti-viral and/or anti-parasitic activity, each to a greater or lesser degree. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Ciclosporine, and its structure is given in The Merck Index, 11th Edition; Merck and Co., Inc.; Rahway, N.J., USA (1989) under listing 2759. Later cyclosporins to be identified are cyclosporins B, C, D and G which are also listed in the Merck Index under listing 2759. A large number of synthetic analogs are also known and representative examples are disclosed in EP 296 122, EP 484 281 and GB 2222770. These compounds are termed collectively xe2x80x9ccyclosporinsxe2x80x9d in this specification.

The pharmaceutical composition exhibits especially advantageous properties when administered orally; for example in terms of consistency and high level of bioavailability obtained in standard bioavailability trials, e.g. 2 to 4 times higher than emulsions. These trials are performed in animals or healthy volunteers using HPLC or a specific or nonspecific monoclonal kit to determine the level of the macrolide in the blood. For example, in the test described in Example 3, 10 mg of rapamycin is administered p.o. to rats and the surprisingly high Cmax values of between 2670 and 3400 ng/ml are detected by ELISA using a specific monoclonal antibody. Also, in the test described in Example 4, an emulsion preconcentrate and a microemulsion preconcentrate composition are found to have much better pharmacokinetic properties than a standard solvent system.
Pharmacokinetic parameters, for example absorption and blood levels, also become surprisingly more predictable and problems in administration with erratic absorption may be eliminated or reduced. Additionally the pharmaceutical composition is effective with tenside materials, for example bile salts, present in the gastrointestinal tract. That is, the pharmaceutical composition is fully dispersible in aqueous systems comprising such natural tensides and is thus capable of providing microemulsion systems in situ which are stable and do not exhibit precipitation of the active ingredient or other disruption of fine particulate structure. The function of the pharmaceutical composition upon oral administration remains substantially independent of and/or unimpaired by the relative presence or absence of bile salts at any particular time or for any given individual.
The pharmaceutical composition is preferably compounded in unit dosage form, for example by filling them into orally administrable capsule shells. The capsule shells may be soft or hard gelatine capsule shells. Where the pharmaceutical composition is in unit dosage form, each unit dosage will suitably contain between 10 and 100 mg of the macrolide, more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg of the macrolide. Such unit dosage forms are suitable for administration I to 5 times daily depending upon the particular purpose of therapy, the phase of therapy and the like.
However, if desired, the pharmaceutical composition may be in drink solution form and may include water or any other aqueous system, to provide emulsion or microemulsion systems suitable for drinking.
The utility of the pharmaceutical composition can be observed in standard clinical tests in, for example, known indications of macrolide dosages giving equivalent blood levels of macrolide; for example using dosages in the range of 2.5 mg to 1000 mg of macrolide per day for a 75 kilogram adult and in standard animal models. The increased bioavailability of the active ingredient provided by the compositions can be observed in standard animal tests and in clinical trials. If a cyclosporin or FK506 compound is included in the pharmaceutical composition, the utility may also be observed in standard clinical tests and animal models. The dosages of macrolide to be used in the clinical tests are as given above while those for the cyclosporin may be in the range of 25 mg to 1000 mg per day and those for a FK506 compound may be 2.5 mg to 1000 mg per day for a 75 kg adult.
The optimal dosage of macrolide to be administered to a particular patient must be considered carefully by the treating physician as individual response to and metabolism of the rapamycin compound may vary. It may be advisable to monitor the blood serum levels of the rapamycin compound by radioimmunoassay, monoclonal antibody assay, or other appropriate conventional means. Dosages of the macrolide will generally range from 2.5 mg to 1000 mg per day for a 75 kilogram adult, preferably 25 mg to 500 mg, with the optimal dosage being approximately 50 to 100 mg per day. Satisfactory results are obtained by administering about 75 mg per day for example in the form of two capsules, one containing 50 mg and one containing 25 mg; or three capsules each containing 25 mg. If a cyclosporin or FK506 compound is included in the pharmaceutical composition, the cyclosporin dosage may be 25 to 1000 mg per day (preferably 50 mg to 500 mg) and the FK 506 compound dosage may be 2.5 mg to 1000 mg per day (preferably 10 mg to 250 mg).
The pharmaceutical compositions are particularly useful for the following conditions:
a) The treatment and prevention of organ or tissue transplant rejection, for example for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants. The pharmaceutical compositions are also indicated for the prevention of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
b) The treatment and prevention of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific autoimmune diseases for which the pharmaceutical compositions may be employed include, autoimmune hematological disorders (including e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn""s disease) endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy) and juvenile dermatomyositis.
c) The treatment and prevention of asthma.
d) The treatment of multi-drug resistance (MDR). The rapamycin compounds suppress P-glycoproteins (Pgp), which are the membrane transport molecules associated with MDR. MDR is particularly problematic in cancer patients and AIDS patients who will not respond to conventional chemotherapy because the medication is pumped out of the cells by Pgp. The pharmaceutical compositions are therefore useful for enhancing the efficacy of other chemotherapeutic agents in the treatment and control of multidrug resistant conditions such as multidrug resistant cancer or multidrug resistant AIDS.
The rapamycin compounds also exhibit anti-tumour and antifungal activity and hence the pharmaceutical compositions can be used as anti-tumour and anti-fungal agents.
In a further aspect the invention also provides a process for the production of a pharmaceutical composition as defined above, which process comprises bringing (1) a hydrophilic phase; (2) a lipophilic phase; and (3) a surfactant into intimate admixture and adding the compound of the macrolide class. When required, the composition may be compounded into unit dosage form, for example filing the composition into gelatine capsules.
Optionally further components or additives, in particular a hydrophilic phase co-component, for example ethanol, may be mixed with components (1), (2) and (3) or with or after addition of macrolide.
The composition may be combined with sufficient water or sufficient of an aqueous solvent medium such that a microemulsion or emulsion is obtained.
The contents of all the references referred to above especially the exemplified compounds are hereby incorporated by reference, and each of the exemplified compounds may be used as a macrolide in the examples listed below.
The following examples illustrate compositions in unit dosage form, suitable for use, for example in the prevention of transplant rejection or for the treatment of autoimmune disease, on administration of from 1 to 5 unit dosages/day. The examples are described with particular reference to rapamycin but equivalent compositions may be obtained employing any other macrolide.


A method for improving critical dimension uniformity of a wafer includes exposing a plurality of mask patterns on a first plurality of substrates at predetermined locations with common splits conditions of focus and exposure dose for each of the first plurality of substrates to form a plurality of perturbed wafers; measuring a critical dimension of the plurality of mask patterns at each of the predetermined locations for each of the plurality of perturbed wafers; averaging the critical dimension measured at each of the predetermined locations over the plurality of perturbed wafers to form a perturbed critical dimension map; measuring a sidewall angle of the plurality of mask patterns; averaging the sidewall angle measured to form a perturbed sidewall angle map; and providing the perturbed critical dimension map and the perturbed sidewall angle map to an exposure tool.

The present disclosure relates in general to semiconductor manufacturing technology, and more particularly, to a method and system for improving critical dimension uniformity in a semiconductor wafer.
As the critical dimensions of semiconductor devices become smaller and smaller, the resolution of the exposure tool used to create the device becomes a more important consideration for manufacture. One way to increase the resolution is to reduce the exposure wavelength. However, reducing the exposure wavelength results in a relatively high manufacturing cost due to changes needed for masks, lenses, and resists. Another way to increase the resolution is to increase the numerical aperture of the projection lens used in the exposure tool. However, one side effect of increasing the numerical aperture of the projection lens is that the depth of focus becomes smaller as the numerical aperture becomes higher. Thus, the focus of the exposure tool becomes an important issue to control.
In order to control the focus, the focus must first be correctly determined. One method for determining focus is the introduction of phase-shift mask monitors, which includes adding a phase shifter adjacent to overlaying marks and measuring a defocus-induced image displacement on an overlay metrology tool. In addition to phase-shifters, phase grating may be used to further enhance the focus sensitivity. While these methods provide focus monitoring, special mask types are required to achieve a desired specific imaging property. Thus, it is costly to use these techniques in a production environment.
A need exists for a method and system that provides a model-based focus monitoring technique from within the process tool which reflects true production process conditions regardless of mask types.

Method and system for improving critical dimension uniformity

Taiwan Semiconductor Manufacturing Company, Ltd.


Provided herein relate to modified or mutant forms of cytolysin A (ClyA) and compositions comprising the same. In particular, the modified or mutant forms of ClyA permits efficient capture and/or translocation of a target negative-charged molecule or polymer through the modified or mutant ClyA nanopores at low or physiological ionic strengths. Thus, methods for using the modified or mutant forms of ClyA and compositions, for example, for characterizing a target negatively-charged analyte, e.g., a target polynucleotide, are also provided.

Transmembrane pores (e.g., nanopores) have been used to identify small molecules or folded proteins and to monitor chemical or enzymatic reactions at the single molecule level. The electrophoretic translocation of DNA across nanopores reconstituted into artificial membranes holds great promise for practical applications such as DNA sequencing, and biomarker recognition. However, translocation of double-stranded or single-stranded DNA through nanopores having internal surface facing negatively charged amino acids are not efficient. In particular, in nanopores having a negative internal surface charge and radii comparable to the Debye length of the solution, the surface potential produced by the electric-double layer (EDL) on the inner nanopore walls overlaps, resulting in a large electrostatic barrier for the entry of DNA into the nanopore. As a consequence, the translocation of DNA across such nanopores has only been observed using large nanopores (e.g., 10 nm) or using small nanopores (e.g., ˜3.5 nm) in high ionic strength solutions or under asymmetry salt concentrations.

Modified nanopores, compositions comprising the same, and uses thereof


A credit card system and method for configuring a vehicle specific to a user and for transacting financial transactions, the system comprising a User Preference and Information Database containing information specific to said user for configuring a specific vehicle, a credit card capable of storing financial transaction information and information to access said User Preference Database, a credit card data receptacle located in said vehicle, a global communication network, a User Transaction History Database containing information about said user""s prior transactions, a display monitor located in said vehicle, and a point of sale where said credit card is used for a financial transaction.

The present invention relates to a credit card and more specifically to a credit card system and method that allows a user to use a credit card for a financial transaction and to customize a vehicle specific for a user of the credit card.
Credit cards and bank debit cards currently exist for financial transactions. These cards are becoming so well used that almost all places of business accept credit cards and bank debit cards for payment. For example, instead of paying inside of a gas station or seeking out a gas attendant to pay for gas, credit cards and debit cards are used at a gas pump for self-service gasoline purchases. These cards are also used to make phone calls from pay phones and while in-flight on an airplane. To simplify purchases at stores, self-service devices are now installed at check-out registers. To assist a user in obtaining cash, Automatic Teller Machines (ATMs) now allow users to deposit, withdraw, and transfer funds to and from bank accounts without interacting with an employee of a bank.
Many of these cards include a magnetic strip, attached to the back of the credit card, which contains information about a credit card owner""s account. During a financial transaction, the magnetic strip is passed through a magnetic card reader so that the information contained on the magnetic strip can be read. Usually, when a credit card is used, the information from the magnetic strip is transmitted, usually over telephone lines, to a credit card company or another authorization service to obtain authorization for a particular purchase.
For individuals who use generally complex equipment, such as mobile assets including on-road or off-road vehicles, ships, airplanes, railroad locomotives, trucks, and other forms of complex equipment including industrial equipment, consumer appliance equipment, medical imaging equipment, equipment used in industrial processes, telecommunications, aerospace applications, power generation, etc., where a number of the complex equipments are available, such as a vehicle which is part of a fleet of vehicles, for example a fleet of trucks, buses, or trains, and the individual is not guaranteed to always use the same piece of complex equipment, the individual has to adjust settings on the specific equipment to the individual""s specifications.
For example, when traveling, instead of traveling with a significant amount of money, an individual will use a credit card to purchase food, lodging, and other items. When such individuals utilize assorted vehicles within a fleet of vehicles, the need to make purchases is juxtaposed with the desire to configure the vehicle to the user""s liking. Because the vehicle used by a specific user is part of a fleet, the user may not use the same vehicle every time. Thus, at a minimum, the user must adjust the climate controls, seating position, steering wheel position, preprogrammed radio stations and other adjustable features to the user""s specific liking.
Towards this end, a user of a credit card or debit card would benefit from a card which in addition is integral in financial transaction, is also able to be used to customize equipment to a user""s specifications. Thus this invention discloses a credit card system for use by a user for conducting financial transactions and configuring features in a vehicle specific to said user. The credit card system comprises a credit card with storage space capable of storing information needed for a financial transaction and information needed to configure a vehicle specific to a user of the credit card, with a credit card data receptacle located in the vehicle. The system also has a User Preference Database, a global communication network, and respective network transceivers. The network transceivers are used for communicating over the global communication network, where they are connected to the credit card data receptacle and the User Preference Database.
This invention also discloses a method for configuring a complex equipment specific to a user with a credit card. The method has a User Preference Database. The method provides for entering a credit card into a receptacle connected to the complex equipment. The method further allows for the credit card to retrieve complex equipment setting data specific to the user from the User Preference Database. The method provides for configuring the complex equipment based on the data received.

Multi-use credit card for financial transactions and vehicle configuration


This invention relates to a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid (xcexcreceptor) agonist, such as fentanyl, or a salt thereof, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity. A process for preparing such a composition and the use of such a composition as an analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication, for the induction of anesthesia, as a sedative and/or for the treatment of anxiety are also provided.

This invention relates to a pharmaceutical composition in the form of a fast dispersing dosage form and to a process for preparing such a composition. The invention also relates to the use of such a composition as an analgesic for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication for the induction of anesthesia as a sedative and as a treatment for anxiety.
Fentanyl (N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide) is a potent synthetic opioid (xcexc receptor) agonist, related to pethidine, which possesses a fast onset and a moderate duration of action. The agonists useful in the present invention are chemical substances capable of combining with a receptor on a cell and initiating a reaction or activity that is characteristics of opiate narcotics, but which is not derived from opium.
Fentanyl, like other opioid agonists, interacts predominantly with xcexc binding sites in the brain, spinal cord and other tissues. Its principal pharmacological actions of therapeutic value are analgesia and sedation and, in this respect, fentanyl is approximately 100 times more potent than morphine and 7,500 times more potent than pethidine. It is therefore primarily used for its analgesic properties as a component of anesthesia and is normally administered by intravenous or intramuscular injection, although transdermal and transmucosal dosage forms have also been developed.
When administered by the intravenous route, the onset of activity is almost immediate and the duration of analgesia is about 30 to 60 minutes after a single dose of up to 0.1 mg. Following intramuscular administration of fentanyl, the onset of activity is 7 to 8 minutes with a duration of activity of 1 to 2 hours. Intravenous fentanyl may therefore be utilized for analgesic action of short duration during the anesthetic periods of premedication, induction and maintenance and in the immediate postoperative period (recovery room) as the need arises. It may also be used as a narcotic analgesic supplement in general or regional anesthesia and, with a neuroleptic agent such as droperidol, as an anesthetic premedication for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. In selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopaedic procedures, it may also be used as an anesthetic agent with oxygen.
Typical dosages for use as a premedication or postoperatively are 50 to 100 xcexcg/kg of body weight. When used as an adjunct to general anesthesia, doses may range from 2 xcexcg/kg to 20-50 xcexcg/kg depending upon the complexity and duration of the operation.
Intravenously administered fentanyl tends to accumulate in skeletal muscle and fat from where it is slowly released into the blood. Repeated doses therefore lead to accumulation and prolonged activity. The plasma protein binding decreases with increasing ionization of the drug and alterations in pH may therefore affect the distribution of fentanyl between plasma and the central nervous system. Fentanyl is primarily transformed in the liver and a high first pass effect is therefore observed when the drug is administered by non-parenteral routes. However, about 75% of an intravenous dose of fentanyl is recovered in the urine with less than 10% as the unchanged drug, the main metabolites being norfentanyl and despropionylfentanyl which are both inactive.
In addition to analgesia, fentanyl may cause alterations in mood, euphoria, dysphoria and drowsiness. Moreover, therapeutic levels of fentanyl may cause nausea and vomiting directly by stimulation of the chemoreceptor trigger zone. However, nausea and vomiting are significantly more common in ambulatory than in recumbent patients.
One of the most serious adverse effects associated with use of intravenous fentanyl is hypoventilation. This is seen as a reduction in the respiratory rate (breaths per minute) and in the oxygen saturation level of the blood. Indeed, this hypoventilation may last longer than the analgesic effect. It is therefore necessary to ensure that an opioid antagonist, intubation equipment and oxygen are readily available when fentanyl is injected.
Fentanyl may also cause muscle rigidity, particularly in the muscles of respiration. This may occur in the postoperative period and patients should therefore be carefully monitored, especially those receiving a high dose of fentanyl. Should this effect occur, it may be reversed by administration of naloxone or overcome by neuromuscular-blocking drugs.
As with other opioid agonists, fentanyl increases the tone and decreases the propulsive contractions of the gastrointestinal tract leading to constipation. However, at therapeutic dosages, fentanyl exerts minimal effects on the cardiovascular system, although orthostatic hypotension and fainting may occur in some patients and vagally-mediated bradycardia has been reported.
The transdermal dosage form is available as a range of patches offering a range of release rates from 25 to 100 xcexcg of fentanyl per hour over 3 days. In this dosage form, fentanyl is released as a free base. The actual amount released from the patch varies with time and also between patients. Essentially, the skin absorbs fentanyl and a depot of fentanyl concentrates in the upper skin layers. The serum fentanyl concentrations gradually increase until levelling off with peak serum concentrations being attained between 24 and 72 hours. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration. After removal of the patch, the serum fentanyl concentrations gradually decline with levels falling by 50% in about 17 hours. This slower elimination, as compared to that after intravenous administration, is due to continued absorption of drug from the depot in the skin after removal of the patch.
In view of the above, the transdermal patch is indicated for the management of chronic pain in patients who require continuous opioid analgesia for pain that cannot be managed by paracetamol-opioid combinations, non-steroidal analgesics or PRN dosing with short acting opioids. It is not indicated for the management of acute or postoperative pain because of the risk of hypoventilation (4% incidence) and should not be administered to children under 12 unless used in an authorized research setting.
The oral transmucosal system consists of a lozenge of fentanyl citrate attached to a handle. The lozenge is sucked until complete dissolution is achieved (normally within about 12 to 15 minutes). A bioavailability study of this device in comparison with intravenous and oral solution administration showed that the absolute bioavailability from the device was 51%, as compared to 32% from the oral solution, and that the tmax was also faster from the device. It is estimated that about 75% of the total dose from the device is swallowed and a third of this amount reaches the systemic circulation in addition to the 25% of the dose which is absorbed sublingually.
The oral transmucosal device has been approved for use for anesthetic premedication in children and adults and for use in anesthesia or monitored anesthesia care. The approved dose for this dosage form for premedication is between 5-15 xcexcg/kg (400 xcexcg) for adults. However, this product is only authorized for administration in hospital settings where there is immediate access to life support equipment, including oxygen, facilities for endotracheal intubation, intravenous fluids and opioid antagonists. Also, there is a restriction on personnel authorized to administer this product.
This device is clearly unsuitable for use during and after operations and can therefore only be used for some of the indications for which the intravenous injection form can be used. Also, although several clinical trials have shown that the oral transmucosal device is generally useful as a premedicant in children prior to surgery, there is a high incidence of adverse effects, some of which could complicate the induction of anesthesia.
The main adverse effect is mild facial pruritus (incidence of about 50 to 60%) but the occurrence of nausea and vomiting has also been high (30 to 50%). Indeed, the high incidence of vomiting in one study in children led to the termination of the study and is probably the most troublesome side-effect. Moreover, pre-treatment with an anti-emetic has not proved to be effective in decreasing the incidence of nausea and vomiting. In addition, the device has also been shown to reduce oxygen saturation levels in blood in some children, thus necessitating constant blood oxygen monitoring in patients taking the product. There are thus significant drawbacks with respect to the adverse event profile which may limit the clinical usefulness of the oral transmucosal device form of fentanyl in some settings as a premedication before surgery.
Approval has been sought for the use of the transmucosal device in the treatment of breakthrough pain in chronic pain patients already receiving opioid therapy in home or hospital settings. The regulatory authorities have expressed concern regarding the incorporation of a potent and narcotic drug into a device, which looks like a child""s confectionery product. It is feared that the lollipop form of the product would be attractive to a child, and result in accidental consumption of the narcotic, with potential life-threatening consequences.
It is clear from the above that it would be highly desirable from a clinical point of view to find a way of administering fentanyl and other opioid (xcexc receptor) agonists which is easy for the patient to accomplish and which bypasses first pass metabolism in the liver while still providing good bioavailability of the active ingredient and a rapid onset of activity.
According to the present invention there is therefore provided a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid (xcexc receptor) agonist, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
It has been found that such fast-dispersing dosage forms promote pre-gastric absorption of the active ingredient, that is, absorption of the active ingredient from that part of the alimentary canal prior to the stomach. The term xe2x80x9cpre-gastric absorptionxe2x80x9d thus includes buccal, sublingual, oropharyngeal and oesophageal absorption. An opioid (xcexc receptor) agonist, such as fentanyl, absorbed by such pre-gastric absorption, passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of an opioid (xcexc receptor) agonist, such as fentanyl, absorbed in this way may also be increased. This means that the dose of fentanyl or other opioid (xcexc receptor) agonist may be reduced while still producing the desired beneficial effects and this decrease in dose will result in a corresponding reduction of unwanted side effects.
One example of a fast-dispersing dosage form is described in U.S. Pat. No. 4,855,326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a xe2x80x9ccandy-flossxe2x80x9d preparation. The spun xe2x80x9ccandy-flossxe2x80x9d product is then compressed into a rapidly dispersing, highly porous solid dosage form.
U.S. Pat. No. 5,120,549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
U.S. Pat. No. 5,079,018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0xc2x0 C. or below to leave spaces in place of hydration liquid.
Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air or vacuum drying.
U.S. Pat. No. 5,298,261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.
EP-A-0627218 discloses a fast-dispersing dosage form which comprises a tablet comprising a sugar alcohol or the like as principal ingredient which is prepared by the wet granulation method in which a kneaded mixture of the sugar alcohol or the like with a drug is compression molded before drying.
Published International Application No. WO 94/14422 describes a process for drying frozen discrete units in which the solvent is removed under conditions whereby the solvent is evaporated from the solid through the liquid phase to a gas, rather than subliming from a solid to a gas as in lyophilization. This is achieved by vacuum drying at a temperature below the equilibrium freezing point of the composition at which point the solvent (such as water) changes phase.
The term xe2x80x9cfast-dispersing dosage formxe2x80x9d, as used herein and in the claims, refers to compositions which disintegrate/disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity. It therefore encompasses all the types of dosage forms described in the preceding paragraphs as well as any other equivalent dosage form. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.
In the case of the preferred type of fast-dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.
Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalarnine.
One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable coloring agents include red, black and yellow iron oxides and FDandC dyes such as FDandC Blue No. 2 and FDandC Red No. 40 available from Ellis and Everard. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweeteners include aspartame, acesulfame K and thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.
The compositions of the invention comprise an opioid (xcexc receptor) agonist as an active ingredient. Representative drugs within this class include, but are not limited to, alfentanil, codeine, diamorphine, dihydrocodeine, fentanyl, hydromorphine, methadone, morphine, morphine-6-glucoronide, oxymorphine, pethidine, sufentanil and tramadol and salts of these compounds. Such drugs are commercially available and their routes of administration and dosage rates are reported in the literature.
Thus, there is disclosed a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid agonist characterized in that the composition is in the form of a fast dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
A preferred active ingredient for use in the invention is fentanyl or a salt thereof. If a salt is used, it is preferred that the salt is an acid-addition salt of fentanyl, especially the citrate salt. However, since it is known that the un-ionized form of fentanyl penetrates mucosal membranes better than the ionized form, the composition of the invention may be buffered to a suitable pH range typically 7 to 7.5 by addition of an acid or alkaline substance.
The active ingredient is generally present in the composition in an amount from 0.2 to 95%, normally 1 to 20%, by weight of the composition of dried dosage form. Generally the active ingredient is present in an amount from 0.1 to 200 mg, normally 0.2 to 20 mg per dose depending upon the particular drug.
When the active ingredient is fentanyl it is preferably incorporated in the composition in an amount of from 0.5 to 10% by weight of the dried dosage form.
According to another aspect of the invention there is provided a process for preparing a pharmaceutical composition as previously defined which comprises bringing a carrier into association with the active ingredient.
In a further aspect, the invention provides the use of a fast-dispersing dosage form designed to release active ingredient rapidly in the oral cavity to deliver an opioid (xcexc receptor) agonist, such as fentanyl, or a salt thereof. A method of administering an opioid (xcexc receptor) agonist, such as fentanyl, or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition as previously defined is also provided.
The invention also provides, in another aspect, a composition as defined above for use as an analgesic. The composition is particularly useful for the treatment of chronic pain, especially in a patient already receiving opioid therapy. In this respect, it is envisaged that the composition of the invention could provide the possibility of more individual titration of dose when required when the pain is most severe, especially during the night.
It is estimated that about 29% of patients with cancer continue to experience moderate to severe pain despite analgesic therapy and this can occur as intermittent breakthrough pain, often due to increases in a patient""s activity level. Attempts to counteract this type of pain by increasing the dose of long-acting formulations of analgesics often produce slow onset of analgesia and unwanted side-effects of sedation, constipation or nausea and vomiting. However, the composition of the invention provides a rapidly acting, potent analgesic which would reduce the pain for the required time and then wear off fairly quickly thereby minimizing the side-effects of the active ingredient. Accordingly, the invention also provides a composition for use in the treatment of breakthrough pain in a patient experiencing chronic pain.
The composition of the invention is easier and quicker to administer than any of the existing dosage forms of fentanyl and other opioid (xcexc receptor) agonists. Thus, it is also suitable for administration in situations where an anesthetic, sedative or anxiolytic effect is required and the patient is conscious. The invention therefore also provides a composition for use as an anesthetic premedication, for the induction of anesthesia, for use as a sedative and/or for the treatment of anxiety.
According to a further aspect of the invention there is also provided the use of a composition as defined above for the manufacture of a medicament for use as an analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication, for the induction of anesthesia, as a sedative and/or for the treatment of anxiety.
A method of treating pain, especially chronic pain or breakthrough pain, or anxiety is also provided which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition as previously defined.
The invention also provides a method of inducing an anesthetic effect or a sedative effect in a patient which comprises introducing into the oral cavity of the patient a pre-determined amount of a composition as previously defined calculated to induce anesthesia or sedation respectively in the patient.

Opioid agonist in a fast dispersing dosage form


A method of using scrap rubber and other scrap materials, such as tires or parts or pieces of tires, to manufacture or melt steel and other metals in a furnace is disclosed. The scrap rubber may be used as a carbon source for the manufacture of steel and other metals, and may be used as an energy source to melt the scrap metal used to make the steel and other metals. The net benefit of this method includes reducing the amount of scrap rubber, such as tires, to be sent to a waste disposal facility or landfill, thereby improving the environment. In addition, by increasing the use of scrap rubber as a source of energy for steel or metal production, less energy is required from other sources.

It is known to use scrap tires, or parts of tires, as a supplemental fuel source and carbon source for steel melting in an electric arc furnace. The techniques and methods of such use are described in U.S. Pat. No. 5,322,544 and U.S. patent application Ser. No. 09/974,199, both of which are in the name of Franklin Leroy Stebbing and both of which are incorporated herein by reference in their entirety. As described in U.S. Pat. No. 5,322,544, recycling scrap tires into steel or using them as a heat source improves the environment by removing the tires from landfills where they do not degrade but do create a fire hazard. Additionally, a single scrap tire, weighing about 20 pounds, has about the same heating value of coke, approximately 15,000 BTU's per pound, or approximately, 300,000 BTU's per tire. In the manufacture of steel, scrap tires, which are so plentiful that they have a near zero cost, can be used as a substitute to coal or coke as the heating source, thereby significantly reducing the costs to manufacture the steel. As described in U.S. patent application Ser. No. 09/974,199, the scrap tires can be bundled with scrap steel in a charging bucket and then the contents of the bucket placed in the furnace where the bundled tires and scrap steel are recycled into steel. The present invention described herein builds upon the known techniques and methods of using scrap tires or scrap rubber in the manufacture of steel, as set forth in U.S. Pat. No. 5,322,544 and U.S. patent application Ser. No. 09/974,199.

This patent is subject to a terminal disclaimer.

Methods of using tires and scrap rubber in the manufacture and melting of steel and other metals


An improved stick preparation is provided which is made up of at least two separate phases and at least one phase contains spherical polymer particles which can contain a pigment. The particles provide smoothness to the preparation and can be used to provide an interesting visual appearance to the stick.

This invention relates to a cosmetic and dermatological preparation in the form of a stick for applying a composition dimensionally stable at ambient temperature and spreadable at body temperature to the skin, this composition comprising two or more gel phases of different composition.
Two-phase stick preparations based on alcoholic soap gels have been known for some time, cf. for example DE-AS 1 122 221. Preparations such as these make is possible to introduce individual constituents which are incompatible with other components into one phase of the stick and thus to prevent unwanted interactions with the components of the second phase. The storage stability of the stick preparations can also be increased by introducing the more readily volatile or oxidation-sensitive components into the core or into one of the inner phases of the stick.
However, problems arise out of the fact that the contact between the two phases can lead to interactions between the phases, more particularly to the bleeding of individual components into the other phase. In order to prevent this, DE-A-2 752 420 proposes a two-phase antiperspirant stick which comprises a core of an oil solidified with waxes and an outer phase or jacket of a polyol soap gel.
These known stick preparations are unsatisfactory both in their sensorial properties and in their performance properties. Above all, they do not solve the problem of effectively preventing individual components of two-phase soap gel sticks from bleeding from one phase into the other phase.
Another problem to be solved was to develop multiphase stick preparations with a particularly attractive, aesthetically satisfactory appearance and improved sensorial properties.
According to the invention, this problem has been solved by dispersing a porous powder of spherical polymer particles in one of the gel phases. Microspheres such as these can also be charged with sensitive active ingredients, readily volatile perfumes or dyes so that these components are stabilized.
Accordingly, the present invention relates to a stick preparation of a composition which is dimensionally stable up to 40xc2x0 C., can be spread onto the skin and melts at temperatures above 40xc2x0 C. and which consists of two or more separate gel phases of different composition which contain monohydric or polyhydric alcohols, gelling agents, perfumes, cosmetic or dermatological principles and optionally water and galenic auxiliaries, a porous powder of spherical polymer particles being dispersed in one of the gel phases in a quantity of 0.1 to 10% by weight, based on that phase.
In addition, the stick preparation according to the invention can be made aesthetically very attractive through differences in the transparency, coloring or pigmenting of the phases. The spherical polymer particles improve skin feel where corresponding sticks are used on the skin by increasing the lubricating effect and reducing tackiness. Finally, it has been found that perfumes and cosmetic principles can be at least partly absorbed in the porous polymer particles and released to the skin again under control, i.e. over a prolonged period. This slow-release effect can be enhanced by initially charging the porous polymer particles during their production with the perfumes and active principles and introducing them thus charged into the gel phase.
In the context of the present invention, the expression xe2x80x9cgel phasexe2x80x9d is understood to be a composition which comprises a liquid phase that has been solidified by a gelling agent. The liquid phase may consist of water, monohydric and polyhydric alcohols containing 2 to 8 carbon atoms and mixtures thereof. Suitable agents for gelling these liquid phases are surfactants which, dissolved in the liquid phase, form a network structure and thus solidify the liquid phase to form the gel. Gelling agents such as these are, for example, the metal salts of fatty acids, preferably those containing 12 to 22 carbon atoms, fatty acid amides, fatty acid alkanol-amides, dibenzal sorbitol and certain polymers, for example alcohol-soluble polyamides and polyacrylamides, or mixtures of these gelling agents. Preferred gelling agents are the alkali metal, alkaline earth metal, aluminium and amine soaps of C12-22 fatty acids, for example sodium stearate, sodium palmitate, magnesium stearate or aluminium stearate.
Preferred polyhydric alcohols are polyols containing 2 to 8 carbon atoms and 2 to 6 hydroxyl groups, for example ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 2-methyl propane-1,3-diol, glycerol, erythritol, penta-erythritol, trimethylol propane, sorbitol, methyl glucoside, cyclohexane triol or inositol. Suitable monohydric alcohols are, for example, ethanol, n-propanol and isopropanol. Preferred components of the liquid phase are ethanol, 1,2-propylene glycol, butane-1,3-diol, glycerol, sorbitol and mixtures thereof, optionally even in admixture with water.
The gel phases additionally contain perfumes or cosmetic or dermatological principles.
Suitable perfumes or perfume oils include individual perfume compounds, for example synthetic products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Perfume compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert.butyl cyclohexyl acetate, linalyl acetate, dimethyl benzyl carbinyl acetate, phenyl ethyl acetate, linalyl benzoate, benzyl formate, ethyl methyl phenyl glycinate, allyl cyclohexyl propionate, styrallyl propionate and benzyl salicylate. The ethers include, for example, benzyl ethyl ether; the aldehydes include, for example, the linear alkanals containing 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal; the ketones include, for example, the ionones, xcex1-isomethyl ionone and methyl cedryl ketone; the alcohols include anethol, citronellol, eugenol, geraniol, linalool, phenyl ethyl alcohol and terpineol and the hydrocarbons include, above all, the terpenes and balsams. However, mixtures of various perfumes which together produce an attractive perfume note are preferably used.
Perfume oils such as these may also contain natural fragrance mixtures obtainable from vegetable or animal sources, for example pine, citrus, jasmine, lily, rose or ylang-ylang oil. Other suitable perfume oils are essential oils of relatively low volatility which are generally used as aroma components, for example sage oil, camomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, lime blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil and labdanum oil,
Suitable cosmetic principles are, above all; substances which have a favorable effect on the aesthetic properties of the skin, more particularly on its smoothness and suppleness, on skin moisture, on perspiration and body odor and on the coloring or browning of the skin and on its protection against the harmful effects of the environment, more particularly sunlight.
Preferred cosmetic principles for the stick preparations according to the invention are, above all, deodorizing and perspiration-inhibiting substances. These are understood above all to be antimicrobial substances which have an inhibiting effect on perspiration-decomposing microorganisms or enzyme-inhibiting substances which inhibit the perspiration-decomposing esterase enzyme. Suitable antimicrobial agents are, for example, 2,4,4xe2x80x2-trichloro-2-2xe2x80x2-hydroxydiphenyl ether (Triclosan(copyright)), chlorhexidine gluconate, phenoxyethanol, pentane-1,5-diol, hexane-1,6-diol, antimicrobial essential oils and farnesol. Suitable lipase inhibitors are, for example, triethyl citrate and triacetin. Perspiration-inhibiting astringent substances compatible with the gel phase may also be present iii the stick preparations. Suitable antiperspirant agents are, for example, sodium aluminium chlorohydroxylactate, which is marketed under the name of Chloracel(copyright), and other astringent substances.
Dermatological principles are generally understood to be substances which have a healing effect or preventive effect on diseases of the skin. Suitable dermatological agents are, for example, local anaesthetics, antibiotics, antiphlogistics, antiallergics, corticosteroids, sebostatic agents and other locally acting pharmaceutical agents.
Vitamins, panthenol, allantoin, plant extracts and proteins with dermatological activity, including for example octoxyglycerol, may also be present as active principles.
Porous powders of spherical polymer particles have long been used in cosmetics as a component of skin-care compositions because they have a favorable effect on the smoothness of the skin and can prevent tackiness (cf. EP 105 657 A1 and EP 409 690 B1). There are also various known processes for producing microspheres such as these from various monomers, for example by special polymerization processes or by dissolving the polymer in a solvent and spraying the solution into a medium in which the solvent is able to evaporate or to diffuse from the particles. One such process is known, for example, from EP 466 986 B1. Suitable polymers are, for example, polycarbonates, polyurethanes, polyacrylates, polyolefins, polyesters and polyamides.
The production of porous microspheres by special polymerization processes is described, for example, for polyamides in DE-A-2 160 125, EP 192 515 B1 and EP 303 530 B1. In the processes described in these documents, fillers, for example pigment particles, may also be added to the polymerization mixture so that porous microspheres of polyamides filled with fillers or pigment particles can be produced in this way. A process for producing microspheres from inert particles, for example pigments, coated with polyamide is also described in EP 196 972 B1.
Preferred porous powders of spherical polymer particles contain a core of a pigment particle, for example of titanium dioxide. Through polymer powders such as these, a white or colored, optionally pearlescent color effect can be introduced into the clear gel phase, providing the two-phase stick preparation according to the invention with an attractive appearance.
The porous powders of spherical polymer particles optionally comprising a pigment core preferably have a mean particle size of 0.5 to 50 xcexcm and a specific surface of 1 to 20 m2/g. Polymer powders such as these are commercially available, for example under the name of Microthene(copyright) (U.S.J. Chemicals) in the case of of polyethylene, under the name of Miralite(copyright) (Pierce and Stevens Chem. Corp.) in the case of polyvinylidene chloride or under the name of Orgasol(copyright) (ATOCHEM SA) in the case of polyamide (Nylon). Other known commercial products are, for example, polyacrylates (Polytrap(copyright), Dow Corning), polymethacrylates (Micropearl(copyright), SEPPIC), polyethylenes and polypropylenes (Accurel(copyright), Akzo).
According to -the invention, a particularly preferred two-phase stick preparation contains spherical polymer particles with a core of pigment, preferably titanium dioxide, in a quantity of 30 to 60% by weight, based on particle weight. One such product based on polyamide is obtainable, for example, as Orgasol(copyright) 1002 Ex D Weixcex2 10 Cos from Lehmann and Voss and Co., Hamburg.
The gel phases of the multiphase sticks according to the invention preferably consist of soap gels and contain
20 to 90% by weight of monohydric or polyhydric alcohols containing 2 to 6 carbon atoms,
4 to 14% by weight of fatty acids containing 12 to 22 carbon atoms in the form of their metal or amine soaps,
0.1 to 30% by weight of perfumes or cosmetic or dermatological principles and optionally water and typical galenic auxiliaries.
Typical galenic auxiliaries in the context of the invention are substances which are normally added to stick preparations of the type in question to influence consistency, transparency, abrasion or stability. Corresponding auxiliaries are, above all, surface-active substances, for example emulsifiers, solubilizers and dispersants. In addition, thickeners, for example water-soluble polymers, layer silicates, pyrogenic silica, electrolyte salts, such as KCl, NaCl, complexing agents, for example EDTA tetrasodium salt, and other auxiliaries are used.
The gel phases of the multiphase stick preparation according to the invention are preferably very similar in composition and, for the most part, differ only in their color, transparency, content of polymer powder and the active principles present therein.
In another preferred embodiment, the porous powder of spherical polymer particles is charged with perfumes or cosmetic or dermatological principles. This is preferably done by incorporating the microspheres in the gel in the form of a dispersion in monohydric or polyhydric alcohols in which the perfumes or active principles are also present.
A delayed release of the perfumes and active principles on the skin and hence a prolonging of the effect on the skin are achieved in this way. In addition, unwanted interaction with other components of the gel phase is prevented in this way.
Totally different or incompatible active principles may also be incorporated in the stick composition in this way providing part of the polymer powder is charged with one active principle and another part of the polymer powder is charged with another active principle and the polymer powders thus differently charged are introduced into the same phase of the stick composition.
In one particularly preferred embodiment, the stick composition is present in the form of two or more concentrically arranged phases of which the inner phase or one of the inner phases contain(s) the dispersed powder of spherical polymer particles. The outer phase is preferably transparent and optionally lightly colored. Aesthetically particularly attractive stick preparations are obtained in this way. Corresponding stick preparations can be produced, for example, by initially forming the core by pouring the gel liquefied by heating into a mold, allowing it to cool and gel, removing it from the mold, introducing it into a wider mold and then forming the outer phase or jacket by pouring the gel liquefied by heating into the space between the core and the mold wall, allowing it to cool and gel and removing it from the mold.
A similar process comprises initially forming the outer phase/jacket by pouring the liquefied gel into an annular mold with a removable cylindrical core, allowing it to cool and gel and removing the core and then pouring the liquefied gel of the core into the cylindrical space of the jacket thus formed and leaving it to harden.
In principle, the core does not have to be cylindrical in shape and may even assume the form of a cone or frustum or a helix. In order to simplify production, the phases may advantageously be arranged parallel to the longitudinal axis of the stick.
In this case, it is possible in principle to use the continuous processes known from the technology of soap production for producing multicolored soap strands of differently colored soap compositions in order to produce a single strand of two or more gels which can be cut into sticks of any length. Corresponding processes for producing strands of concentrically arranged phases are, for example, the coaxial extrusion processes known from AT-PS 198 501 and DE-AS 2 526 917. Other processes for producing multiphase strands of phases arranged parallel to the longitudinal axis (but not concentric phases) are described in U.S. Pat. No. 3,268,970.
The multiphase stick preparations produced in this way are preferably introduced into a tube with a bottom piston designed for displacement longitudinally of the tube axis by a pushing, turning or pressure mechanism of the type typically used for deodorant sticks and other cosmetic sticks. In this way, the stick can be conveniently handled without the fingers coming into direct contact with the stick.