Briefly described, embodiments of this disclosure include ink composition for use in electrostatic imaging, method of making an ink formulation for use in electrostatic imaging, and the like.

Various techniques for electrostatic image transfer are known. One method includes the use of an intermediate transfer member. A liquid image, which includes a liquid carrier having ink particles dispersed therein, is transferred from a photoconductive surface of a photoconductive member or drum to a surface (e.g., a release layer or blanket) of the intermediate transfer member. The liquid image is attracted from the photoconductive surface to the surface of the intermediate transfer member. The liquid carrier is removed from the surface of the intermediate transfer member and the ink particles are compacted on the surface in the image configuration. Thereafter, the ink particles are transferred from the surface of the intermediate transfer member to a substrate in the image configuration by electrostatic attraction.
Modern liquid toner electrostatic imaging began with the invention of a new class of toners referred to as ElectroInk™. This type of toner (also referred to as ink formulation) is characterized by its toner particles being dispersed in a carrier liquid, where the toner particles include a core of a polymer with fibrous extensions extending from the core. When the toner particles are dispersed in the carrier liquid in a low concentration, the particles remain separate. When the toner develops an electrostatic image, the concentration of toner particles increases and the fibrous extensions interlock. A large number of patents and patent applications are directed toward this type of toner (e.g., U.S. Pat. Nos. 4,794,651; 5,047,306; 5,208,130). It has been discovered that this type of toner allows for high quality offset printing at high speed. This type of printing is described the following U.S. Pat. Nos. 4,678,317; 4,860,924; 4,980,259; 4,985,732; 5,028,964; and 5,034,778.
However, the toners currently used include deficiencies relating to scratch resistance, rub resistance, and substrate adhesion. Therefore, a need exists in the art for ink formulations improve scratch resistance, rub resistance, and/or substrate adhesion.

Ink formulations and methods of making ink formulations

Hewlett-Packard Development Company, L.P.


An oral contraception regimen which comprises sequentially administering two or more progestational agents exhibiting different effects on the human endometrium in combination with an estrogen. The invention is also directed to an extended use oral contraception regimen comprising the sequential administration of two or more progestational agents in combination with an estrogen.

The present invention is directed to a combination hormonal regimen for human oral contraception. More particularly, the present invention is directed to an oral contraception regimen which comprises sequentially administering two or more progestational agents exhibiting different effects on the human endometrium in combination with an estrogen. The invention is also directed to an extended use oral contraception regimen comprising the sequential administration of two or more progestational agents in combination with an estrogen.
Oral contraception formulations, containing a combination of a progestin and an estrogen, have been known for some time. A number of different regimens for controlling ovulation and conception with these hormones have been developed. Conventional regimens may provide consistent dosage of either an estrogen or progestin or both throughout the period of administration, or they may vary the amount of estrogen or progestin by increasing or decreasing the dosage employed during the period of administration. For instance, U.S. Pat. Nos. 4,616,006 and 4,390,531 disclose triphasic oral contraception regimens wherein the dosage of progestin is varied in three sequences during the 21 day administration period in an effort to minimize side effects and optimize contraceptive activity.
A disadvantage inherent in the current oral contraception regimens is the incidence of abnormal intermenstrual or xe2x80x9cbreakthroughxe2x80x9d bleeding. In general, the intended bleeding pattern with oral contraceptives is usually predictable and occurs during the seven day drug free interval following 21 days of active drug administration. Breakthrough bleeding refers to incidences of bleeding or spotting during the 21 day administration period. Breakthrough bleeding or spotting is reported to occur in about 20-30% of women. The incidence of breakthrough bleeding is the highest during the first few months of treatment and appears to be related to the dose and nature of the hormonal components as well as idiosyncratic responses. Another related problem with conventional oral contraceptive regimens is the occurrence of early withdrawal flow which is any bleeding or spotting during the drug administration interval which continues without interruption into the period wherein drug administration is withdrawn. Since discontinuation of a method of contraception because of abnormal intermenstrual bleeding continues to be an important factor leading to drug discontinuation and unintended pregnancy, there is a need for combined oral contraceptive formulations that meet the various clinical demands of the user and which provide the most acceptable pattern of bleeding.
Extended use regimens have been investigated wherein oral contraceptives are administered for up to three months between cycles. A three month trial of a regimen of oral contraceptives that reduces the frequency of menstruation was first described by Loudon, N B, Br.Med.J. 1977;2:487-90. The advantages of such regimens are that they offer freedom from menstrual flow and premenstrual symptoms for extended periods of time and are generally easier to follow. Such extended use regimens may also have therapeutic use in dysmenorrhea, menorrhagia, premenstrual-type symptoms and menstrual migraine. Sulak et al., Obstet-Gynecol 1997;89: 179-83 in a restropective analysis, reports that 74% of the patients treated with 6 weeks of continuous active pills were stabilized and that the extended oral contraceptives regimen delayed the onset and severity of reported complaints. However, such extended use regimens are hampered by a high incidence of breakthrough bleeding, which is a common cause for discontinuation of the regimen.
Accordingly, there is a need for an oral contraceptive treatment regimen which reduces the incidence of bleeding abnormalities. As will be seen, there is also a related need for an oral contraceptive treatment regimen which achieves this reduction in the incidence of bleeding abnormalities while exhibiting a favorable effect on endometrial morphology.
There is also a need for an extended use oral contraceptive treatment regimen which achieves effective contraception but which exhibits a reduced incidence of bleeding abnormalities.
Different progestins in combined oral contraceptives appear to be associated with different bleeding patterns. While the mechanism for bleeding irregularities is still poorly understood, applicants have observed different patterns of breakthrough bleeding and spotting in comparative studies of the combination oral contraceptives norgestimate/ethinyl estradiol versus levonorgestrel/ethinyl estradiol. The variation in the bleeding patterns was more pronounced in those patients who were not taking oral contraceptives in the cycles prior to the study. In general, the overall proportions of breakthrough bleeding episodes were similar, but the patterns differed.
Progestational agents also differ in their effects on the endometrium. This can range from a proliferative or secretory endometrium to a non-vascular or atrophic condition which can resemble the postmenopausal histological structure. These effects are manifested by morphological changes in the endometrial glands, spiral capillaries, endometrial stroma and epithelial tissues. Cycle control during oral contraceptive use is related to the pattern of endometrial maturation. Thus, depending on the progestational agent used, one can detect histological differences between preparations which could subsequently influence the bleeding patterns. The endometrial morphology appearance has been observed to be different between norgestimate and levonorgestrel formulations. After six months treatment with norgestimate/ethinyl estradiol, well preserved lining epithelium was observed corresponding to midcycle or early secretory phase of the normal menstrual cycle. (Rabe, T. et al, Gerbutsch Fauenheilk 1986,46:883). Norgestimate was found to have an endometrial sparing effect in primates in comparison to other progestins. (Wilborn, WH et al, 1984, 4th Annual Meeting of Ala. Academy of Science, Tuscaloosa, Ala.). In general, the findings during treatment in humans with norgestimate containing oral contraceptives indicate a secretory transformation of well developed endometrium which was found however incapable of supporting an implanted blastocyte. In contrast, women treated with levonorgestrel containing oral contraceptives generally exhibit atrophic endometrial appearance with diminished gland diameter and glandular epithelial.
The present invention relates to a combination progestin and estrogen hormonal method and regimen for human contraception involving the sequential administration of two or more different progestational agents in combination with an estrogen comprising the steps of:
(a) administering a contraceptively effective amount of an endometrial sparing progestin in combination with an estrogen in single daily doses for a period of 7-14 days followed by;
(b) administering a contraceptively effective amount of an atrophizing progestin in combination with an estrogen in single daily doses for a period of 7-14 days;
(c) repeating steps (a) and (b) for a period of 21-90 days;
(d) withdrawing the administration for a period of 6-8 days; and
(e) repeating steps (a)-(d) continuously.
In a further embodiment, the invention provides a method of reducing breakthrough bleeding resulting from the administration of an effective ovulation suppressing amount of a combination progestin/estrogen oral contraceptive comprising administering an atrophizing progestin for 7-14 days, followed by administering an endometrial sparing progestin for 7-14 days and repeating this cycle for a period of 21-90 days before withdrawing the oral contraceptive for 6-8 days.
In a further embodiment, the invention relates to a method of reducing bleeding abnormalities in an extended use trimonthly oral contraceptive treatment regimen in accordance with the above regimen wherein the oral contraceptive is administered for a period of about 90 days prior to withdrawal.
Another aspect of the invention relates to a pharmaceutical package in the form of a tablet dispenser containing single daily doses of the combination oral contraceptive designed to administer the above mentioned method.
In accordance with the present invention, a combination progestin oral contraceptive regimen is provided which involves alternating an endometrial sparing progestin with an atrophizing progestin at intervals which may alter endometrial morphology thereby reducing breakthrough bleeding by preventing both irregular shedding of atrophied endometrium and the breakdown of very glandular endothelium in the later phases of continuing stimulation. By providing a balance of these two effects in sequential phases, the method may permit prolonged intervals between withdrawal bleeds.
The term xe2x80x9cEndometrial Sparingxe2x80x9d progestin means any compound which exhibits progestational activity and which induces a secretory endometrial morphology with a well preserved glandular structure. Examples of endometrial sparing progestins are norgestimate and norethindrone.
As used herein, the term xe2x80x9catrophizing progestinxe2x80x9d refers to any compound which exhibits progestational activity and which induces an atrophic endometrial morphology with diminished gland diameter and glandular epithelial. Examples of atrophizing progestins are desogestrel, gestodene and levonorgestrel.
As stated, applicants have observed different bleeding patterns associated with different progestins. In a randomized comparative study of norgestimate/ethinyl estradiol (NGM/EE 250/35) versus levonorgestrel/ethinyl estradiol (LNG/EE 150/30), different patterns of breakthrough bleeding and spotting were observed. In general, the overall proportions of bleeding episodes were similar, however, the patterns (i.e. when in the cycle the episode occurred) were different. Thus, by making use of this observation concerning the difference in bleeding patterns and the knowledge of the different endometrial morphology associated with the different progestins, a method of reducing the incidence of breakthrough bleeding is obtained by combining the use of progestins exhibiting these different characteristics in the manner of this invention.
In accordance with the present invention, the combination progestin oral contraceptive composition is administered for a period of 21-90 days. This is followed by a period of 6-8 days in which the hormones are withdrawn to allow normal menstruation. Day one of the cycle is defined as the first day of administration. The days are then numbered sequentially until the hormone is withdrawn and menstruation occurs. A placebo or other hormone-free agent such as an iron supplement may be administered during the withdrawal phase.
The combination progestin contraceptive composition of the present invention comprises 21-90 separate dosage units intended for single daily dosage administration. The composition consists essentially of; a first phase of 7-14 dosage units containing an atrophizing progestin in combination with an estrogen in admixture with a pharmaceutically acceptable carriers; a second phase of 7-14 dosage units containing and endometrial sparing progestin in combination with an estrogen and a pharmaceutically acceptable carrier and, optionally, additional phases of alternating atrophizing progestin and endometrial sparing progestin in combination with an estrogen for a total period of 21-90 days. The composition may optionally contain 6-8 daily dosage units of hormone free units. The dosage and nature of the estrogen component will generally remain constant throughout the cycle while the nature of the progestin is sequentially alternated. The dosage of the progestin in each phase may also be varied as necessary to achieve maximum effect.
Any conventional estrogen may be employed as the estrogenic component of the combination oral contraceptive of the present invention. Preferably, the estrogen component is employed in a daily dosage equivalent to about 0.020-0.050 mg of ethinyl estradiol, preferably about 0.030 mg ethinyl estradiol equivalent.
The progestin component is preferably administered in a daily dosage corresponding in progestational activity to 0.065-2.0 mg norethindrone per day. The dosage of the progestin component may also be varied in biphasic or triphasic sequences so that less progestin is administered in the early stage of administration with increasing dosages utilized in the latter stages of administration. For example, a biphasic dosage may be utilized wherein the dosage of endometrial sparing progestin administered in the first phase of administration may correspond in progestational activity to 0.065-0.75 mg norethindrone per day, while the dosage of atrophizing progestin administered in the second stage may range in progestogenic activity from 0.25-2.0 mg norethindrone per day. Similarly, the dosage of progestin may be adjusted in a triphasic manner as disclosed in U.S. Pat. Nos. 4,616,006 and 4,390,531. It may also be desirable to administer the estrogen component alone for the first 1-7 days of administration following the onset of menses as disclosed in U.S. Pat. Nos. 4,921,843 and 5,280,023.
The combination progestin regimen of the present invention is particularly useful for trimonthly extended use continuous therapy wherein the hormones are administered continuously for a period of up to three months before administration is withdrawn and withdrawal bleeding occurs. It is contemplated that such a regimen would involve alternating the administration of the endometrial sparing progestin with the atrophizing progestin during the three month period of administration. For example, the endometrial sparing progestin/estrogen combination would be administered for a period of about 7-14 days followed by administration of the atrophizing progestin/estrogen combination for a period of about 7-14 days. The two progestin/estrogen combinations would then be alternated in sequence for the three month extended use period of administration followed by a one week withdrawal flow interval. By alternating the use of the two progestins having differing effects on the endometrium, it is contemplated that the incidence of intermenstrual bleeding would be reduced allowing for the use of the extended regimen with a minimum of adverse effects.
The described dosages are generally preferred, but, of course, may be adjusted to provide the optimal therapeutic response depending upon the requirements of the patient, the weight and age of the patient, the particular hormone combination composition employed and the relative potency of the drugs involved. The determination of optimum dosages for a particular situation is within the skill of the medical arts.
In accordance with the present invention, the estrogen and progestin agents are preferably administered together orally in association with a pharmaceutically acceptable carrier. In general, the active agents may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to about 50% of sugar, and elixirs containing, for example from about 20 to 50% ethanol, and the like, together with the usual additives or vehicles, in accordance with generally acceptable pharmaceutical practice. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. While the estrogen and progestin components are preferably combined for oral administration, the estrogen and progestin components may be administered separately or parenterally.
The carrier may be one or more substances which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents as well as encapsulating materials. Suitable solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, talc, magnesium carbonate, kaolin and the like. Suitable liquid carriers include sterile water, polyethylene glycol, non-ionic surfactants and edible oils such as peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents and antioxidant agents, for example, vitamin E, ascorbic acid, BHT and BHA.
The active agents may also administered by other art recognized means as practiced in the pharmaceutical arts. For example, the estrogen and progestin alone or in combination may be formulated for administration transdermally via a skin patch, by intramuscular injection, contained within an inert matrix which is implanted within the body and in a depot state, or intravaginally in a matrix that slowly releases the active compositions.
The active compounds may also be administered parenterally. Solutions or suspensions of the active components can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical compositions are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration. This invention also relates, therefore, to a pharmaceutical package which contains the combination estrogen and progestin active agents in individual dosage units in a synchronized, fixed sequence, wherein the sequence corresponds to the oral contraceptive regimen of the present invention.
For example, the pharmaceutical package can be in the form of a kit containing individual tablets arranged sequentially and consisting of 7-14 single daily doses of the endometrial sparing progestin in combination with the estrogen, followed by 7-14 single daily doses of the atrophizing progestin in combination with the estrogen. This sequence of tablets may be alternated for a total of 21-90 tablets. Finally, the active agent containing tablets may be optionally followed with up to seven placebo tablets so that a tablet may be administered each day continuously.
The method of the present invention can be further understood by the following examples, but should not constitute a limitation thereof.

Combination progestin oral contraceptive regimen


A penetrating concentrate containing a biocidal amount of a biocide uses a penetrating carrier vehicle containing an emulsifiable copolymer of a cyclic diene and a polymerizable, unsaturated glyceride. For biocides, such as iodopropargyl carbamate, which otherwise requires use of significant amounts of co-solvent to disperse, is directly soluble in the copolymer thereby eliminating or at least substantially reducing the need for co-solvents to assure stability of the biocide in the formulation. The concentrate also exhibits a low level of volatile organics.

The invention relates to a rapidly penetrating concentrate containing biocides that do not require significant amounts of co-solvents to stabilize the biocide.
Many architectural and exposed wood surfaces are treated with biocides (a term that includes fungicides, algacides, and insecticides) or other preservatives for protection. Such treatments are typically applied in the form of a penetrating liquid. Generally, these materials are first prepared as a preservative concentrate or concentrate emulsion. The concentrate or concentrate emulsion is then added to a compatible binder along with other components to form either a non-filmforming protectant or a filmforming coating.
A number of biocides and related biocides are used to protect wood against attack. One of the well accepted class of biocides are the iodopropargyl carbamates with 3-iodo-2-propynyl butyl carbamate (xe2x80x9cIPBCxe2x80x9d, CAS No. 55406-53-6) and compounds derived therefrom being the most recognized. IPBC is commercially available in a formulated liquid form from Troy Corporation under the trademark TROYSAN POLYPHASE(copyright). These compounds and their preparation are well described in U.S. Pat. No. 3,923,870; EP 257,888; EP 258,030; and Hansen, xe2x80x9cIPBCxe2x80x94A New Biocide for Wood Protectionxe2x80x9d, Modern Paint and Coatings, November 1984, the disclosures of which are herein incorporated by reference.
Iodopropargyl carbamates have found wide commercial acceptance in paint films; penetrating protectants and stains for wood, leather, paper, cloth, and other materials; adhesives; caulks; paper and plastics coatings; personal care products; and similar filmforming or non-filmforming products. For wood preservatives, IPBC must be present in a concentration of at least 0.5% by total weight to provide biocidal protection. Products like paints or stains should contain IPBC in a quantity within the range of 0.05-0.5% by total weight to provide biocidal protection.
Pure IPBC is a crystalline solid that is insoluble in a wide variety of liquids, as necessary for an effective biocide. Unless products containing IPBC are, however, properly formulated to provide solution stability to the IPBC, tiny needle crystals fall out of solution as the product dries significantly affecting general biocidal protection. See, Hansen, xe2x80x9cIPBCxe2x80x94A New Biocide for Wood Protectionxe2x80x9d, Modern Pain and Coatings (November 1984).
Preservative concentrates of IPBC have traditionally been made with high quantities of one or more co-solvents to provide stability to the IPBC as well as provide a liquid that is soluble in conventional binders. See, e.g., the examples of U.S. Pat. No. 4,276,211 (dipropylene glycol and diacetone alcohol) and U.S. Pat. No. 4,977,186 (co-solvent of ethylglycol acetate or methoxypropyl acetate in water/mineral spirits vehicle). In general, a solvent would be used to dissolve the IPBC, and a co-solvent would be added to stabilize the IPBC/solvent solution in the final preservative formulation. TROYSAN(copyright) POLYPHASE(copyright) AF-1 is a commercial IPBC concentrate that has about 40% IPBC by weight and employs 35 wt % of a co-solvent system of dimethylsulfoxide, high flash naphtha, and dipropylene glycol.
Aside from the added expense, high levels of co-solvents are diluents in the final product, inherently serve to limit the solids concentration that can be prepared, and are a source of volatile organic materials.
It would be useful to have an biocide concentrate for IPBC and structurally similar biocides that would not require high quantities, if any, of co-solvents yet maintain compatibility with the main binder systems used in commercial coatings. In combination, it would be helpful to be able to provide a biocide concentrate that exhibits levels of solubilized, stable biocide that are greater than 2% by total weight of formulated products.
As a complicating factor, binder and carrier systems are under continuing pressure to employ materials with a low volatile organics content (VOC). The emissions from each component of a product formulation will contribute to the total VOC of the product. Even aqueous systems must be concerned about VOC levels.
It would be desirable to have a iodopropargyl carbamate preservative concentrate that exhibited low VOC levels.
Penetration below the surface of a porous substrate is important for providing effective levels of fungus protection. This is particularly true for wood. Unfortunately, aqueous preservative formulations have traditionally been less effective at penetration than nonaqueous solvent-based formulations. For side grain penetration, water in the formulation swells the wood fibers which shrink the interfiber passages and hinder further penetration.
It would be helpful to have an aqueous protectant for wood with high penetration and fungus protection.
It is an objective of the invention to provide an emulsifiable biocide formulation that exhibits reduced or eliminated levels of co-solvents for the biocide yet is compatible with alkyd binder systems used in commercial coatings.
It is an objective of the invention to provide a biocidal concentrate with low levels of co-solvent.
It is an objective of the invention to supply a biocidal concentrate that exhibits low VOC levels.
A still further objective of the invention is to provide an aqueous protectant for wood with high penetration and fungus protection.
In accordance with these and other objectives of the invention that will become apparent from the description herein, the invention provides a penetrating biocide concentrate comprising and, preferably, consisting essentially of:
(a) a biocidal amount of a biocidal compound within the general formula:
xe2x80x83and
(b) a penetrating carrier comprising a cyclic diene crosslinked polymerizable, unsaturated glyceride wherein said concentrate contains less than 35% by weight of added co-solvents for the biocidal compound.
The penetrating biocide concentrate of the invention provides a vehicle for delivering effective amounts of biocide to porous substrates with low VOC in aqueous and nonaqueous protectant systems. On wood, products with the concentrate penetrate the wood surface deeply and provide a high level of biocidal protection. The concentrate can be used directly as a non-filmforming preservative or added as the preservative component in a filmforming coating product.
The present invention is a penetrating biocide concentrate containing (a) a biocidal amount of a biocidal compound within the general formula:
and
(b) a penetrating carrier of a copolymer of a cyclic diene, wherein the concentrate contains levels of co-solvents for the carbamate that are less than otherwise needed in the absence of the penetrating carrier. The penetrating carrier enables low VOC, aqueous or nonaqueous systems to carry iodopropargyl carbamate into porous substrates for protection against fungus attack. The penetrating carrier is particularly useful on cellulosic substrates. The carrier of the invention penetrates deeply into the wood without external pressures or vacuum.
In general, the active biocides useful in the concentrate of the present invention are compounds included within the broadly useful class of compounds within generic Formula I:
Most preferred are iodopropargyl carbamates which follow Formula II:
wherein, for each formula:
R1 is alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkaryl of one to twenty carbon atoms and having 1 to 3 linkages corresponding to m;
R2 and R3 are independently selected from hydrogen or methyl;
m and n are independently selected integers from 1 to about 3; and
R4 is selected from hydrogen and R1.
When R1 is an aryl or alkaryl, the aryl group will have the general formula:
wherein:
X is cyano, nitro, lower alkyl, halogenated lower alkyl, alkoxy of 1-12 carbon atoms unsubstituted or substituted with lower alkyl groups, lower alkenyloxy, unsubstituted or halogenated lower alkynoxy, lower alkoxycarbonyl, or lower alkylthio;
p is zero or an integer of 1 to 6;
n is zero or an integer of 1 to 4; and
the sum of m+n is less than 6.
The preferred biocide is 3-iodo-2-propynyl butyl carbamate.
A biocidally effective amount of biocidally active compound is used in the concentrate to provide protection against attack by fungus, algae, or insects (depending on the specific biocide employed) when applied to the target substrate. The specific amount of biocide applied as a protectant in the final formulation will depend on the specific product, substrate, and environment. Generally, it is sufficient to apply at least enough biocide as is conventional in the art to supply a biocidal efficacy. For fungicides, the amount of applied fungicide will generally be within the range from, based on an activity relative to 3-iodo-2-propynyl butyl carbamate, about 0.05-0.4 kilogram per square meter (kg/m2), preferably about 0.1-0.2 kg/m2. Higher concentrations of biocide can be applied without detrimental effect. Concentrates according to the invention will generally contain up to about 4-5% fungicide, preferably about 1-5% fungicide, and even more preferably about 3-5% fungicide.
The penetrating carrier vehicle used in the present invention is a water emulsifiable, non-filmforming, copolymer in which the biocide is at least 3 wt % soluble. Such copolymers are the result of a polymerization reaction of a cyclic diene, preferably cyclopentadience, and a polymerizable unsaturated glyceride oil. Exemplary glyceride oils such as linseed oil (CAS No. 8001-26-1), marine oil, tung oil, and dehydrated castor oil.
The copolymer preferably is made of 70-90 wt % glyceride oil and 10-30 wt % cyclic diene. When the glyceride is linseed oil, the copolymer is preferably made according to the copolymerization process in U.S. Pat. No. 5,288,805 with 70-90 wt % of a linseed oil exhibiting an iodine value of 170-195 and 10-30 wt % cyclopentadiene to make a copolymer having a viscosity of 500-10,000 cps at 25xc2x0 C. and an average molecular weight within the range of 1200-2600. The copolymerization is conducted at 200xc2x0-300xc2x0 C. for 1-48 hours until the desired viscosity is produced. The disclosure of U.S. Pat. No. 5,288,805 is herein incorporated by reference.
Copolymers of glyceride oils (such as linseed or soya bean oil) and cyclic diene hydrocarbons (e.g., cyclopentadiene) have hitherto been known as useful for filmforming binders for pigments and useful in the fields of adhesives, inks, paints, coatings, and rubber compounding. See, U.S. Pat. Nos. 2,551,387 and 4,330,448 the disclosures of which are herein incorporated by reference. Penetrating carrier vehicles useful in the present invention are commercially available under the tradenames NEWCOWEL(trademark) FLE or NEWCOWEL(trademark) FLE-55 (emulsion form), sold by Ashland-Sxc3xcdchemie-Kernfest Gmbh (4010 Hilden, Reisholzstrasse 16, Germany) and DILULIN(trademark) sold by Cargill, Inc. (Technical Oils Dept., Minneapolis, Minn. USA).
The penetrating biocide concentrate of the invention can be used as the sole binder for a non-film forming coating as well as the protective component in paint films and penetrating protectants and stains for wood, leather, paper, cloth, and other porous materials. Because the amount of co-solvents is significantly reduced or eliminated altogether, penetrating protective compositions according to the present invention can be made to carry greater than 30% solids, preferably about 50 to 100%, and more preferably about 80-98% by weight of solids based on the total weight of the coating product.
The concentrate of the invention can also be added to aqueous systems by first forming an emulsified concentrate. Emulsification can be by any conventional method with convention emulsification equipment. See, e.g., U.S. Pat. No. 5,228,905. Suitable devices emulsify with high shear conditions from impinging fluid streams or through ultrasonic energy.
Some amount of co-solvent may be useful to enhance the stability of the biocides in aqueous systems. Suitable co-solvents that can be used include dimethylsulfoxide, high flash naphtha, dipropylene glycol, mono- and dialkyl ethers of ethylene glycol and their derivatives (e.g., Cellosolve(trademark) (ethylene glycol monoethyl ether), butyl Cellosolve(trademark), butyl Cellosolve(trademark) acetate, Cellosolve(trademark) acetate, dibutyl Cellosolve(trademark), n-hexyl Cellosolve(trademark), methyl Cellosolve(trademark), methyl Cellosolve(trademark) acetate, and phenyl Cellosolve(trademark)), TEXANOL(trademark), hexylene glycol, toluene, propylene glycol mono t-butyl ether, tripropylene glycol monomethyl ether, propylene glycol monomethyl ether acetate, mono-and dialkyl ethers of diethylene glycol and their derivatives (e.g., Carbitol(trademark) (diethylene glycol monoethyl ether), butyl Carbitol(trademark), butyl Carbitol(trademark) acetate, Carbitol(trademark) acetate, dibutyl Carbitol(trademark), diethyl Carbitol(trademark), N-hexyl Carbitol(trademark), methyl Carbitol(trademark), and methyl Carbitol(trademark) acetate), dipropylene glycol mono methyl ether, DOWANOL(trademark) PNB, isopropyl alcohol, butyl diglycol, COASOL(trademark) and mixtures thereof.
If co-solvents are employed, concentrates made in accordance with the invention will include less than 35 wt % of such co-solvents, preferably 0-30 wt %, and even more preferably 0-25 wt % co-solvents. Particularly preferred is a penetrating biocide concentrate according to the invention that employs 0-10 wt % co-solvents for stabilizing the biocide in the polymeric binder of the invention.
One or more adjuvants can be used in products made with the present concentrate without materially affecting the solvation relationship between the polymeric carrier and the biocide. Preservative products can also include water sheathing agents (e.g., polytetrafluoroethylene), waterproofimg agents, organic binding agents (e.g., long oil alkyds), additional biocides, auxiliary solvents, processing additives, fixatives, plasticizers, UV stabilizers, dispersion stability enhancers, water soluble or insoluble dyes, white and color pigments or pigment dispersions, corrosion inhibitors, antisettling agents, drying agents, olefin or paraffin waxes that enhance water beading, and anti-skinning agents as well as any other conventional additive for such products. Water emulsifiable drying agents are preferably added to the formulation before emulsification. In aqueous systems, an emulsifier having an HLB value of at least 10 is preferably used. More preferred are emulsifiers with an HLB value of about 11. Suitable penetrating protective compositions are described in commonly owned, copending U.S. patent application Ser. No. 08/132,769 filed on Jul. 11, 1994 the disclosure of which is herein incorporated by reference.
A particularly preferred formulation includes 0.05-1 wt % fumed silica as a waterproofing and dispersion stability enhancer, 5-40 wt % mineral spirits to control the viscosity for ease of application, 0.01-2 wt % of a water sheathing agent such as paraffin waxes, polyolefins, and fluoropolymers as a water sheathing agent, 75-95% penetrating copolymer carrier, 0.01-5 wt % technical grade iodopropargyl carbamate (preferably IPBC), and 0.01-1 wt % of an inorganic ultraviolet protectant. This formulation exhibits deep, rapid penetration of unsealed wood surfaces thereby allowing the carrier to carry biocidally effective amounts of IPBC deeply into the wood for protection thereof.
Compositions containing the concentrate according to the invention can be applied by any conventional method. Such methods include dipping, flow coating, roll coating, brushing, wiping, and the like.


A method of making a tubulation-free gas filled electrode or lamp having the steps of providing a glass or quartz tube having a first end and a second end opposite the first end; inserting a cathode into the first end; crimping the first end thereby securing the cathode and making the first end airtight; securing a solid plug inside the tube second end but leaving a gap between the plug and tube through which gas can pass; evacuating air from inside the tube by drawing it through the second end past the plug; charging the tube with a gas; and sealing the plug gap to make the second end airtight.

1. Field of the Invention
The invention relates to gas filled electrodes and lamps.
2. Description of the Related Art
Gas filled electrodes ("GFEs") are used in many applications, including but not limited to ozone generators and non-thermal dielectric barrier discharge reactors. GFE designs are derived from common gas filled lamp designs with which they share many features. One of the undesirable features of GFEs is the tubulation common to all existing GFE designs and to gas discharge lamps in general.
The tubulation feature results from the need to evacuate air from the lamp or GFE interior volume, and then charge that volume with the desired gas or gases. This evacuation and charging is accomplished by attaching a small tube to an opening in the lamp or GFE wall. Air is removed and gas inserted through the small tube, which is subsequently fused shut and broken or twisted off while softened by heating.
The tubulation produces a small protrusion from the GFE wall, which is more fragile than the balance of the GFE wall. Designing a reliable GFE necessitates protecting that weakness from damage. Accomplishing that protection leads to dimensional and manufacturing complications in the design.
Even with compensating design measures, the underlying weakness remains. What is needed, therefore, is a GFE or lamp and method of evacuating air and inserting desired gas that does not produce a tubulation.

Tubulation-free gas filled electrode or lamp


A computer painting system is provided for a graphic computer system that has at least one touch screen apparatus and at least one display. A stylus having a tip formed of a solid piece of a resiliently compliant non-conductive material is used to apply variable pressure on the surface of the touch screen apparatus. Software executing on the computer system interprets the variable pressure applied to the surface of the touch screen apparatus and generates corresponding graphic images on the display. Preferably, the tip of the stylus is formed of a silicone material that allows the tip to easily move across the touch screen apparatus in a way that simulates a conventional painting brush stroke but without leaving a buildup of material on the touch screen apparatus. In one embodiment, the touch screen apparatus and the display are incorporated together in the same device. In another embodiment, the touch screen apparatus is a palette physically separate from the display and operably connected to the computer system.

The present invention relates generally to the field of graphic computer input devices. More specifically, the present invention relates to a passive paint brush stylus formed of a solid piece of a resiliently compliant non-conductive material that interacts with a touch screen display of a computer painting system to provide a computer input system that more closely replicates the actions of conventional painting.
The most popular input devices for computers are the keyboard and mouse. In the field of graphic computer input devices, however, the use of alternative input devices is well known. There are numerous systems that use a passive stylus or pen in connection with a touch screen or digitizing pad. These types of input systems are particularly popular as a way of recognizing handwriting input. A recent example of these types of input systems can be found in U.S. Pat. No. 5,990,875. The passive stylus for these types of input systems is a rigid pen-like device with a somewhat rounded point at the tip of the stylus. This is because the goal of these input systems is to accurately digitize and discriminate the particular spot being indicated by the tip of the stylus and to allow for easy movement of the stylus across the screen or input pad without the stylus being so sharp as to damage the screen or input pad. In one of the more popular applications as an input device for recognizing handwriting for a personal digital assistants (PDAs), it is also important that the stylus be relatively inexpensive so that it can be easily replaced if lost.
While this type of rigid passive stylus is well suited for point recognition applications such as handwriting recognition, it is not well suited to replicating the techniques of conventional painting. In a conventional painting process, the bristles in the tip of a paint brush carry the paint across a surface and create various marks depending upon the size of the brush, the pressure and speed with which the brush is moved across the surface and the angular orientation of the brush relative to the surface. Alternative paint tools such as spatulas or palette knives carry the paint on a surface of the flat tip of the tool that is then spread across the surface in a manner similar to a bristle paint brush; however, the marks made by a spatula or knife on the surface are generally distinct from those created by a conventional bristle paint brush. A silicone paint brush tool that can more closely replicate the manner and strokes as applied by a conventional bristle paint brush is described in U.S. Pat. No. 5,542,144. In contrast to the point oriented nature of a rigid passive stylus, each of these painting tools distributes paint on the surface being painted in a spreading fashion that results in variable width, thickness and density of paint being applied to the surface. As a result, it is difficult to replicate the performance of such painting tools in the context of a graphic computer input device using a rigid passive stylus.
A number of systems have been developed that utilize an active stylus as part of a graphic computer input system in an effort to more closely replicate the results of conventional painting techniques. In contrast to the passive stylus, an active stylus has some electronic or optical components in the stylus that interact with the computer and input screen as part of the graphic input system. For example, U.S. Pat. Nos. 5,420,607 and 5,646,650 describe an electronic paintbrush and color palette that allow a user to generate images on a CRT screen in a manner that imitates conventional painting by using an electronic stylus with fiber optic bristles embedded in the tip of the stylus. A microprocessor in the stylus scans the CRT screen to determine position, angular orientation and pressure of the stylus relative to the screen and communicates this information to the computer controlling the CRT screen to control the generation of images on the screen. Other examples of input systems that use an active or intelligent stylus coupled to a computer are described in U.S. Pat. Nos. 5,155,813, 5,343,220, 5,528,266, 5,557,301, 5,581,052, 5,635,683, 5,959,616 and 5,977,958. Examples of a pressure-sensitive stylus or pen connected to a computerized graphic system that mixes or combines certain predetermined colors, such as the primary colors, on an electronic palette arrangement are described in U.S. Pat. Nos. 4,524,421 and 5,343,220. U.S. Pat. No. 5,861,878 describes a graphic input system that utilizes a mouse input, but represents a graphically modeled painting brush with elastic bristles on the display screen. The obvious problem with such active stylus systems is that the stylus must be relatively complicated and must be coupled in some manner to the computer and display screen. This complexity increases the cost of the system and can interfere with the ability of the system to emulate conventional painting techniques.
A few patents have attempted to use a passive stylus in a manner that imitates conventional painting techniques, rather than as a point entry device for handwriting recognition or the like. U.S. Pat. No. 5,434,959 describes a system for generating variable width lines in which the pressure exerted by a rigid passive stylus or pen on a pressure sensitive tablet and, specifically, for addressing the problem of how to maintain the width of a line as the pen is removed from the tablet. U.S. Pat. No. 5,488,204 describes a paint brush stylus for a capacitive touch sensor pad. The paint brush stylus is comprised of conductive fibers held together at the tip of the stylus like a conventional paint brush. This patent teaches that neither resistive nor acoustic wave touch screens are suitable for simulating conventional painting techniques. Instead, the conductive fibers of the paint brush stylus interact with a capacitive touch-sensor pad to simulate paint-like strokes on a display associated with the capacitive touch-sensor pad.
Despite the various attempts to replicate the process of conventional painting techniques for a computer graphic input system, a simple, economical and accurate representation of conventional painting techniques has yet to be developed for a computer graphic input system.
The present invention is a computer painting system in which a graphic computer system has at least one touch screen apparatus and at least one display. A stylus having a tip formed of a solid piece of a resiliently compliant non-conductive material is used to apply variable pressure on the surface of the touch screen apparatus. Software executing on the computer system interprets the variable pressure made on the touch screen apparatus and generates corresponding graphic images on the display. Preferably, the tip of the stylus is formed of a silicone material that allows the tip to easily move across the touch screen apparatus in a way that simulates a conventional painting brush stroke but without leaving a buildup of material on the touch screen apparatus. In one embodiment, the touch screen apparatus and the display are incorporated together in the same device. In another embodiment, the touch screen apparatus is a palette physically separate from the display and operably connected to the computer system. Preferably, the touch screen apparatus is a surface acoustic wave touch screen device.
In a preferred embodiment, the palette is provided with a spectral color wheel and a plurality of selected color pads and mixed color pads representing available colors to be applied, as well as buttons for controlling applied color attributes such as color consistency, texture, mixing, loading, translucence and blendability. In another embodiment, a scanner is utilized to generate input color data for the palette. Multiple different renditions of the palette may be cataloged and saved for subsequent use to allow a user to build up a repertoire of specifically chosen palettes.

Computer painting system with passive paint brush stylus


A cloth accessory and methods for the use thereof are disclosed and described. In one aspect, the cloth accessory may include a cover member forming an enclosure with a cavity therein, and a cloth attached to the cover member. The cloth may have a first configuration wherein the cloth is retracted substantially into the cover member, and a second configuration wherein the cloth is extended substantially out of the cover member without becoming detached therefrom.

A number of devices benefit from the use of a cloth or other absorbent device for cleansing or polishing. Particularly, those devices that employ one or more lenses, such as glasses, goggles, high power magnification scopes, cameras, binoculars, safety glasses, sunglasses, etc., require periodic, or even frequent cleaning and maintenance in order to maintain suitable visibility therethrough. This is especially true when such devices are used in an outdoor setting during certain activities, such as skiing, hiking, snow mobiling, fishing, hunting, motorcycling, and climbing, among others. In fact, the enjoyment, feasibility, and safety of many activities is often directly dependent on the use of various lens-bearing devices. For example, most hunting activities benefit from the use of a high powered magnifying scope, and skiing almost always requires the use of glasses or goggles. Further, safety glasses are required in most laboratory and industrial arts environments.
Proper maintenance and treatment of a lens-bearing device can be critical. In fact, a number of situations may arise where the lens-bearing device may require cleaning or treatment during an activity in which it is being used. While most lenses are best cleaned with a soft cloth such as a microfilament fabric, in order to avoid scratching, more often than not, due to inconvenience and a lack of forethought, no such cloth is available for use during the activity. Therefore, the lens will either remain dirty, perhaps impairing its function and posing a potential hazard, or being cleaned with whatever fabric is closest at hand, such as a portion of a shirt, coat, etc., which may lead to scratching.
As such, a suitable device for cleaning, or treating the lenses of a lens-bearing device, that is handy, convenient, inexpensive, and easy to use during a variety of activities and in various settings, continues to be sought.

This patent is subject to a terminal disclaimer.


Topical gelled compositions comprising a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a polymer matrix, and methods of treating sexual dysfunction, including both male and female sexual dysfunction, using said compositions.

This invention relates to the preparation of a transdermal delivery system. The preparation is designed to deliver therapeutic levels of a drug which causes vasodilation, and optionally prostaglandin E1, to specific sites below the dermal level of the skin. Specifically, the preparations address sexual dysfunction caused by impotency in males and vaginal dryness in females.
Over the years, methods have been developed to achieve the efficient delivery of a therapeutic drug to a mammalian body part requiring pharmaceutical treatment. Use of an aqueous liquid which can be applied at room temperature as a liquid but which forms a semi-solid gel when warmed to body temperature has been utilized as a vehicle for some drug delivery since such a system combines ease of application with greater retention at the site requiring treatment than would be the case if the aqueous composition were not converted to a gel as it is warmed to mammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC(copyright) polyols are used in aqueous compositions to provide thermally gelling aqueous systems. Adjusting the concentration of the polymer provides the desired sol-gel transition temperature, that is, the lower the concentration of polymer, the higher the sol-gel transition temperature, after crossing a critical concentration minimum, below which a gel will not form.
In U.S. Pat. Nos. 4,474,751 and 4,478,822, drug delivery systems are described which utilize thermosetting gels; the unique feature of these systems is that both the gel transition temperature and/or the rigidity of the gel can be modified by adjusting the pH and/or the ionic strength, as well as by the concentration of the polymer.
Other patents disclosing pharmaceutical compositions which rely upon an aqueous gel composition as a vehicle for the application of the drug are U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780. Thermosetting gel systems are also disclosed for application to injured mammalian tissues of the thoracic or peritoneal cavities in U.S. Pat. No. 4,911,926.
Ionic polysaccharides have been used in the application of drugs by controlled release Such ionic polysaccharides as chitosan or sodium alginate are disclosed as useful in providing spherical agglomerates of water-insoluble drugs in the Journal of Pharmaceutical Sciences, Volume 78, Number 11, November 1989, Bodmeier et al. Calcium alginate gel formulations have also found use as a matrix material for the controlled release of herbicides, as disclosed in the Journal of Controlled Release, (1986), pages 229-233, Pfizer et al.
In U.S. Pat. No. 3,640,741, a molded plastic mass composed of the reaction product of a hydrophilic colloid and a cross-linking agent such as a liquid polyol, also containing an organic liquid medium such as glycerin, is disclosed as useful in the controlled release of medication or other additives. The hydrophilic colloid can be carboxymethyl cellulose gum or a natural alginate gum which is cross-linked with a polyol. The cross-linking reaction is accelerated in the presence of aluminum and calcium salts.
In U.S. Pat. No. 4,895,724, compositions are disclosed for the controlled release of pharmacological macromolecular compounds"" contained in a matrix of chitosan. Chitosan can be cross-linked utilizing aldehydes, epichlorohydrin and benzoquinone.
In U.S. Pat. No. 4,795,642, there are disclosed gelatin-encapsulated, controlled-release compositions for release of pharmaceutical compositions, wherein the gelatin encloses a solid matrix formed by the cation-assisted gelation of a liquid filling composition incorporating a vegetable gum together with a pharmaceutically-active compound. The vegetable gums are disclosed as polysaccharide gums such as alginates which can be gelled utilizing a cationic gelling agent such as an alkaline earth metal cation.
While the prior art is silent with respect to aqueous drug delivery vehicles and isotonicity thereof, osmotic drug delivery systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chamber compartment for holding osmotic agents, adjuvants, enzymes, drugs, pro-drugs, pesticides, and the like. These materials are enclosed by semipermeable membranes so as to allow the fluids within the chambers to diffuse into the environment into which the osmotic drug delivery system is in contact. The drug delivery device can be sized for oral ingestion, implantation, rectal, vaginal, or ocular insertion for delivery of a drug or other beneficial substance. Since this drug delivery device relies on the permeability of the semipermeable membranes to control the rate of delivery of the drug, the drugs or other pharmaceutical preparations by definition, are not isotonic with mammalian blood.
Finding a suitable drug delivery vehicle for the treatment of erectile dysfunction has proven to be particularly difficult. Male erectile dysfunction, the persistent inability of a man to achieve or maintain an erection sufficient for satisfactory sexual performance, is estimated to affect up to 30 million men in the United States. See xe2x80x9cOral Sildenafil in the Treatment of Erectile Dysfunctionxe2x80x9d, New England Journal of Medicine, 338:20:1397 (1998). There are numerous causes of male erectile dysfunction. For example, it may be atonic, due to paralysis of the motor nerves without any evidence of lesions to the central nervous system, particularly the spinal cord. Alternatively, it could be psychic, and dependent on a mental problem or instability. Finally, it could be symptomatic, due to some other disorder, such as injury to nerves in the perineal region, by virtue of which the sensory portion of the erection reflex is blocked out.
Various available treatments have been employed in the treatment of male erectile dysfunction, including vacuum-constriction devices, intracavernosal injections of vasoactive agents, transurethral delivery of prostaglandin E1 (alprostadil), oral administration of sildenafil citrate (Viagra(copyright) available from Pfizer), implantation of penile prostheses, and venous or arterial surgery. Most of these treatments involve painful procedures with varying degrees of success that are often associated with numerous side effects. Moreover, many persons are not candidates for one or more of these treatments as a result of their physiological condition. For example, oral admistration of sildenafil citrate is contraindicated for individuals currently taking organic nitrates, such a nitroglycerine. See xe2x80x9cVIAGRA(copyright) (sildenafil citrate) Tabletsxe2x80x9d, Pfizer Labs, 7 (1998).
The medications most commonly used to treat male erectile dysfunction have been papaverine hydrochloride, a smooth muscle relaxant, phentolamine mesylate, an xcex1-adrenergic blocker, and several other drugs which are used because of their ability to cause vasodilation. Recent data have suggested that prostaglandin E1 either alone or in combination with papaverine produces an improved erectile response. The use of these drugs often requires special applicators, which besides being cumbersome, are also painful to use. However, the use of topical gels, creams and ointments for treating impotency has been proposed in several publications.
U.S. Pat. No. 5,583,144 discloses compositions for relieving erectile impotence in men which contain piperoxan in a pharmaceutically acceptable carrier. As the pharmaceutically acceptable carrier, commercially available gels, ointment and creams, such as the hydrogel, hydroxypropylmethylcellulose are optionally used. The patent does not address the importance of the rate of delivery to the site of action.
U.S. Pat. No. 5,256,652 discloses a topical composition which enhances the maintenance of penis erection and which contains a peripheral vasodilator, an absorption enhancer and, optionally, a vasocontrictor and an alpha receptor combined with a pharmacologically acceptable topical vehicle. The patent discloses that xe2x80x9c[t]he problem with topically administered drugs is their limited penetration of the drug through the skinxe2x80x9d and encourages the use of a skin penetration enhancer. See column 2, lines 59-65. There is no teaching or warning that the rate or amount of absorption may be too high to be effective as the result of drug entering fatty tissue.
U.S. Pat. No. 5,059,603 discloses topical compositions for treating impotence which contain a vasodilator, a vasoconstrictor and an absorption enhancing agent in a pharmaceutically acceptable carrier. The patent also teaches that nicotinyl alcohol may be used as the vasodilator, but that side effects such as flushing and gastrointestinal disturbances may result.
U.S. Pat. No. 4,801,587 discloses a vasodilator or alpha-blocker in an ointment base. However, the patent teaches that a drug carrier is only optionally used when necessary to increase absorption. The patent urges the importance of increasing absorption into the skin while not addressing the proper rate of absorption necessary to attain therapeutically effective amounts at the site of action.
To date there has been little objective data comparing the relative efficacy of the above described medications either alone or in combination. Further, the delivery systems disclosed in the above references have lacked the sophistication necessary to deliver the drug at a rate which provides a therapeutically effective amount at the active site when needed and for an appropriate amount of time. Moreover, the disclosed topical formulations are generally not storage stable.
It is also important to note that sexual dysfunction is not limited to men. Many women, particularly menopausal women, women suffering from an autoimmune disease and women undergoing radiation therapy, experience vaginal dryness caused by loss of normal vulval and vaginal secretions, particularly during sexual activity, resulting in difficulty with or an inability to achieve intercourse. Currently, there are only a limited number of available therapies which address the problem of vaginal dryness. Though in mild cases, local hygiene and antipruritic ointments and creams may be beneficial, typically additional therapy will be necessary. Some currently available therapies involve treatment with hormone-based formulas containing either testosterone or glucocorticoids. Parnell, U.S. Pat. No. 5,380,757, discloses a therapy involving treatments with gamma- linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA). U.S. Pat. No. 4,347,237 discloses a vaginal suppository composed of a variety of different types of water soluble polyoxy alkylene polyol components.
However, the formulations disclosed in the prior art Are all deficient in that the delivery systems which they employ do not carefully control the rate of delivery of the active therapeutic agent which in turn can lead to adverse effects. For example, currently used testosterone treatments can produce clitoral enlargement or other masculinization, and glucocorticoids when used for long periods of time carry a serious risk of producing atrophy and thinning of the epithelium.
A need thus exists for therapeutic compositions for treating sexual dysfunction in men and women that are applied topically and transported through the skin, or administered by injection, without concomitant presence of pain, side effects, high risk of infection, inconvenience or interference with the spontaneity of the sex act and with a highly efficacious result, and methods for using same. Moreover, a need exists for a treatment for erectile dysfunction that may be used in conjunction with cardiovascular agents, such as organic nitrates.
The present invention relates to the formation of gelled compositions and methods for using said gelled compositions in treating sexual dysfunction, including impotency or erectile dysfunction in males, and sexual dysfunction in females caused by vaginal dryness. The methods of the invention comprise topically applying to a specific site on the surface of an animal a therapeutically effective amount of a drug which causes vasodilation dispersed within a gelled composition comprising a polymer matrix which is suspended in a liquid medium, wherein the polymer matrix contains a negative charged polymer blended with a nonionic polymer, and wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:4 to 0.09, and the negative charged polymer is present in amounts of about 1.0% to about 3.5% by weight.
In a preferred embodiment of the invention, the gelled composition contains prostaglandin E1, in addition to the drug which causes vasodilation.
In a further preferred embodiment of the invention, a method for the treatment of erectile dysfunction in a male animal comprises topically applying to the surface of a penis a therapeutically effective amount of a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a gelled composition comprising a polymer matrix which is suspended in a liquid medium; wherein the polymer matrix contains a negative charged polymer blended with a nonionic polymer; and wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:0.5 to 0.09 and the negative charged polymer is present in amounts of about 2.0% to about 3.5% by weight.
In another preferred embodiment of the invention, a gelled composition for treating impotency comprises therapeutically effective amounts of a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a matrix containing a negative charged polymer blended with a nonionic polymer, wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:4 to 0.09 and the negative charged polymer is present in amounts of about 1.0% to about 3.5% by weight.
In yet another embodiment of the invention, a method for the treatment of erectile dysfunction in male animals comprises injecting into the corpora cavernosa a therapeutically effective amount of a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a gelled composition comprising a polymer matrix which is suspended in a liquid medium; wherein the polymer matrix contains a negative charged polymer blended with a nonionic polymer; and wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:4 to 0.09 and the negative charged polymer is present in amounts of about 1.0% to about 3.5% by weight.
In a further embodiment of the invention, a method for the treatment of sexual dysfunction or vaginal dryness in a female animal comprises topically applying to the surface of a vagina a therapeutically effective amount of a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a gelled composition comprising a polymer matrix which is suspended in a liquid medium, and wherein the polymer matrix contains a negatively charged polymer blended with a nonionic polymer, and wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:4 to 0.09 and the negative charged polymer is present in amounts of about 1.0% to about 3.5% by weight In a still further embodiment of the invention, a gelled composition for treating vaginal dryness comprises therapeutically effective amounts of a drug which causes vasodilation, and optionally prostaglandin E1, dispersed within a matrix containing a negative charged polymer having a mean average molecular weight between about 650,000 and 800,000 blended with a nonionic polymer, wherein the molar ratio of the negative charged polymer to the nonionic polymer is 1:4 to 0.09 and the negative charged polymer is present in amounts of about 1.0% to about 3.5% by weight.
It has been unexpectedly discovered that an effective therapeutic level of a drug may be administered topically and transdermally delivered through the skin into various sites where the drug is therapeutically effective. In order for this to be accomplished, it has been discovered that the active drug must be suspended or entrapped in a specially designed polymer matrix containing a specific molar ratio of negatively charged polymers and a non-ionic polymer suspended or dissolved in water and solubilizers.
This system is believed to form a matrix which microencapsulates, suspends, and/or entraps the active drug entity such that when it is administered, it is slowly released into the systemic circulatory system or muscular tissue providing a method of delivering an active drug to an affected site in the body through the skin.
The molar ratio of the polymers present in the matrix is critical in this invention. It has been found that molar ratios of the negative charged polymer to the non-ionic polymer must be from 1:4 to 0.09, and preferably from 1:2.5 to 0.1, and most preferably from 1:0.4 to 0.2. For transdermal delivery of drugs, it has been found that ratios either higher or lower than these levels will result in a polymer shearing effect which produces unacceptable turbulence and air pockets in the composition with resulting loss of potency and efficacy. Furthermore, the solutions tend to separate and form distinct polymer layers when ionic molarity is not appropriate. While gels and other topical therapeutic compositions generally encounter problems with storage stability, the present invention demonstrates an unexpectedly superior storage stability.
At least one of the polymers used to form the matrix of this invention must be sufficiently negatively charged to aid in the dispersion, encapsulation or solubilization of the drug. The viscosity and molecular weight of the negative charged polymer is also critical to the invention. Further, at least one of the polymers of the invention must be a nonionic polymer. The viscosity and molecular weight of the nonionic polymer is also critical to the invention. Particularly preferred nonionic polymers which have a viscosity of about 1,500 for a 5% solution to about 5,500 for a 1% solution have been found to be suitable for forming a polymer matrix capable of transdermal drug delivery. For drug delivery, using nonionic polymers with viscosities below these ranges will result in an excessive rate of release leading to drug dispersion into fatty tissue, causing reduced efficacy, while requiring higher levels of drug with accompanying side effects. Using nonionic polymers with a viscosity above these ranges will result in solid materials which are unsuitable for transdermal drug delivery.
As discussed herein, viscosity, or solution viscosity, refers to the intrinsic viscosity of a polymer in solution (the viscosity which the unassociated polymer molecules give to the solution) and is a function of the molecular weight and very easily measured. Intrinsic viscosity is commonly used for control purposes, and the values can be converted into molecular weight by calibration with osmotic pressure, light scattering, or sedimentation measurements. The viscosity measurements and ranges used herein were provided by Aqualon, a division of Hercules, Inc., in its product specifications for Natrosol(copyright) (hydroxyethyl-cellulose), and all were Brookfield viscosities measured at 25xc2x0 C. It is well within the capabilities of an ordinarily skilled artisan to obtain and/or identify polymers within the ranges specified by the invention.
Particularly preferred negative charged polymers which have mean average molecular weights below about 800,000 and preferably molecular weights between 650,000 to 800,000 have been found acceptable to form usable polymer matrixes for transdermal delivery. Polymers with average molecular weights between 700,000 and 775,000 are most preferred. Polymers having molecular weights above about 800,000 form solid gels in solution and are unable to serve as part of a transdermal delivery system. Furthermore, the polymers must be sterilizable and be stable during sterilization so that the polymer does not lose molecular weight once formulated into the final transdermal delivery form.
Exemplary, non-limiting examples of compounds that may be used as a source of this molecular weight polymer include polysulfated glucosoglycans, glucosaminoglycans, and mucopolysaccharides, derivatives thereof and mixtures thereof. Particularly preferred mucopolysaccharides are chondroitin sulfate and hyaluronic acid salts. Exemplary hyaluronate salts include sodium, calcium, potassium and magnesium salts with hyaluronate sodium being most preferred.
Hyaluronic acid (NAHA) occurs naturally in joint synovial fluid, where it plays a lubricating role, and may have biological activity as well. NAHA is a mucopolysaccharide, and may alternatively be referred to as glucosaminoglycan. The repeating unit of the hyaluronic acid molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glucosamine. Because hyaluronic acid possesses a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions. The D-glucuronic acid unit and N-acetyl-D-glucosamine unit are bonded through a glycosidic, beta (1-3) linkage, while each disaccharide unit is bonded to the next disaccharide unit through a beta (1-5) linkage. The (beta 1-4) linkages may be broken through hydrolysis with the enzyme hyaluronidase.
A variety of substances, commonly referred to as hyaluronic acid, have been isolated by numerous methods from various tissue sources including umbilical cords, skin, vitreous humor, synovial fluid, tumors, hemolytic streptocci pigskin, rooster combs, and the walls of veins and arteries. It is also being synthesized artificially and by recombinant technology.
Conventional methods for obtaining hyaluronic acid results with a product having differing properties and a wide range of viscosities. U.S. Pat. No. 2,585,546 to Hadian, discloses an example of a method for obtaining hyaluronic acid and which involves extracting acetone. washed umbilical cords with a dilute salt solution, acidifying the resulting extract, removing the clot so formed, precipitating some hyaluronic acid with protein from the acidified extract with ammonium sulfate, agitating the liquid with pyridine, precipitating another fraction highly contaminated with protein, followed by more ammonium sulfate which forces some pyridine out of solution along with the high viscosity hyaluronic acid. The hyaluronic acid collects at the interface between the two liquid phases and may be separated by filtration, centrifugation or another usual procedure. A modification of this process involves the fractionation of the acidic salt extract from umbilical cords with alcohol and ammonium sulfate. Alcohol is added to the acidic salt extract, and the resulting precipitate is removed. Solid ammonium sulfate is added to the liquid until saturation and the solution forms two phases with a precipitate of hyaluronic acid at the interface.
U.S. Pat. No. 4,517,296 is directed to the preparation of hyaluronic acid in high yield from Streptococcus bacteria by fermenting the bacteria under anaerobic conditions in a CO2 enriched growth medium, separating the bacteria from the resulting broth and isolating the hyaluronic acid from the remaining constituents of the broth. Separation of the microorganisms from the hyaluronic acid is facilitated by killing the bacteria with trichloroacetic acid. After removal of the bacteria cells and concentration of the higher molecular weight fermentation products, the hyaluronic acid is isolated and purified by precipitation, resuspension and reprecipitation.
One particular fraction of hyaluronic acid (HA) that exhibits excellent matrix formation according to the present invention is hyaluronate sodium having a mean or average molecular weight between 650,000-800,000, preferably 700,000-775,000 with a high degree of purity, 95-105% free, and preferably at least 98% pure, from contamination of related mucopolysaccharides. Furthermore, this hyaluronic acid has a sulphated ash content of less than 15% and a protein content of less than 5%. Examples of usable base salts. include those safe from animal and human use, such as sodium, potassium, calcium, and magnesium salts or the like.
In contrast to HA, chondroitins are mucopolysaccharides comprising repeating units of D-glucuronic acid and N-acetyl-D-galactosamine. Chondroitin sulphates are important components of cartilage and bone and are excellent for preparing the polymer matrix herein.
The negative charged polymers are generally present in the system in amounts which enable a semi-solid gel to be formed. Generally, gels are formed using amounts of about 1.0 to about 3.5% by weight with amounts of about 2.1 to about 2.5% by weight being preferred for use as a topical gel. Concentrations of negative charged polymer greater than 3.5% result in solids which are not suitable for pharmaceutical use.
The solutions used to prepare the gels of the present invention may be prepared in a variety of ways. For example, the polymers may be dissolved in water and purified either separately or jointly and then the optional active drug added to the system.
A particularly preferred procedure involves separately dissolving the nonionic polymer in water and centrifuging the material to form a solution and remove impurities. This may be conveniently done at rotation speeds of 2000 rpm for times of about 30 minutes to about two hours.
In contrast, the negative charged polymer may be blended and stirred in water until it is dissolved. This process must be done while avoiding the formation of bubbles and while freeing the polymer of its electrostatic activity. Furthermore, the molecular weight of the polymer must not be significantly changed during processing and as such mild process conditions are required. Processing conditions of 400-3000 rpm for durations of 16-24 hours have been found acceptable to produce stable solutions or gels of the charged polymer.
Conventional pharmaceutically acceptable emulsifiers, suspending agents, antioxidants (such as sodium meta-bisulfate) and preservatives (such as benzyl alcohol) may then be added to this system. Once all the components are blended together, such as by mixing 400 -3000 rpm for one to four hours, the system is filled into tubes and sterilized. The resulting system is a clear gel which is storage stable for several years.
The drug may be added to the homogenous solution or gel separately once dissolved or disbursed in water. Emulsifiers, suspending agents and preservatives may then be added to this system. One particularly nonlimiting effective material for solubilizing water insoluble drugs is methoxypolyethylene glycol (MPEG). Once all the components are blended together, for 400-3000 rpm for 1 to 4 hours, the system is filled into tubes and sterilized. The resulting system is storage stable for several years.
The formulations may be used topically and also contain conventional pharmaceutically acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives.
As used herein, xe2x80x9cgenital areaxe2x80x9d refers to the general area of a male or female which contains or surrounds the genital organs. The compositions may be directly applied anywhere on the epidermis of the genital area. For highest efficacy in males, the composition should be applied to the epidermis of the penis and testicles. For highest efficacy in females, the composition should be applied directly to the vagina.
As indicated above, the active drug agents may be blended with the aqueous polymer matrix at the time of manufacture. As such, the drug when in the form of a water-soluble solid is simply diluted with sterilized water or polymer matrix solution and prepared in gel form.
The dosage system can be formed with or without the use of pharmaceutically acceptable preservatives. A significant advantage of the dosage form of the present system relates to its ability to allow the drug to slowly diffuse through tissue when administered thus allowing for an effective therapeutic dose to be present for long periods of time, i.e., 15 minutes to several hours.
In this regard, it should be noted that reference to therapeutically effective dose does not necessarily relate to conventional dosage levels, but does relate to drug levels that achieve an effective therapeutic level at the dose employed, which may be the same level but not at the same frequency of administration previously required for drugs taken orally or by injection. This not only significantly reduces the number of doses required to achieve the same effect, but it also reduces costs, maintenance and health hazards associated with conventional treatment therapies.
Doses may vary from patient to patient depending on the type and severity of the condition being treated and the drug being administered. Generally, doses of 150 mcg to 1000 mcg may be administered with preferred doses using 200 to 500 mcg of drug disbursed in the gelled matrix system. The total dosage of the gelled matrix with drug is usually 0.5 ml to 5 ml in volume. When the drug which causes vasodilation is niacin, it preferrably will range from about 1% to about 15% by weight of the total composition. More preferrably, the amount of niacin in the total composition will range from about 2% to about 12% by weight. Most preferrably, the amount of niacin in the total composition will range from about 3% to about 6% by weight. The preferred amount of total composition in each dose will range between about 1 ml and 3 ml. in volume.
There is a physiological basis for the treatment of both male and female sexual dysfunctions together since they have physiological responses in common. See Foreman, U.S. Pat. No. 4,521,421. With regard to male sexual dysfunction, it is generally recognized that primary erectile dysfunction is almost always due to intraphsychic factors. In rare cases, biogenic factors, usually associated with low testosterone levels and reflecting disorders of the hypothalamic-pituitary-gonadal axis, provide the major etiology. Occasionally, vascular abnormalities are found. Physical factors include systemic diseases (e.g., diabetes mellitus [the most common], syphilis, alcoholism, drug dependency, hypopituitarism, and hypothyroidism); local disorders (e.g., congenital abnormalities and inflammatory diseases of the genitalia); vascular disturbances such as aortic aneurysm and atherosclerosis (e.g., Leriche""s syndrome); neurogenic disorders (e.g., multiple sclerosis, spinal cord lesions, pituitary mifcroadenoma with hyperprolactinemia, and cardiovascular accident); drugs such as hypertensives, sedatives, tranquilizers, and amphetamines; and surgical procedures such as sympathectomy, prostatectomy and castration produce varying effects. Impotence is usually not induced by transurethral prostatectomy, whereas it almost always occurs after perineal prostatectomy. However, retrograde ejaculation is produced in the vast majority of men, irrespective of the type of prostatectomy.
Pharmacological erection therapy is an effective method to treat male erectile dysfunction. The medications most commonly used have been papaverine hydrochloride, a smooth muscle relaxant, and phentolamine mesylate, an xcex1-adrenergic blocker. Recent data have suggested that prostaglandin E1 either alone or in combination with papaverine produces an improved erectile response.
There currently is increasing evidence that prostaglandin E1 is presently the single most effective agent for pharmacological erection therapy. The present invention contemplates using prostaglandin E1 as a catalyst to be used in conjunction with a drug which causes vasodilation in cases in which the drug which causes vasodilation may not alone be effective. The combination of a drug which causes vasodilation and prostaglandin E1 in conjunction with the claimed drug delivery system of the present invention provides a highly potent and efficacious therapeutic substance which may induce a response in subjects for whom all other available therapies are ineffective and without side effects or pain. Prostaglandin E1 is a physiological agent that is metabolized locally within the cavernous tissue and there appears to be a low incidence of corporeal fibrosis, priapism or systemic reactions associated with its use. Several studies using subjective evaluation have shown that prostaglandin E1 is more effective than a combination of papaverine and phentolamine. Lee et al. found that two-thirds of the men who failed prior intracavernous therapy with papaverine and phentolamine achieved adequate erections with prostaglandin E1. Prostaglandin E1 has also been found to be extremely effective as a single agent in several other studies. Liu et al. recently reported that prostaglandin E1 is at least as effective as papaverine in increasing penile blood flow measured by duplex sonography. Prostaglandin E1 has the advantage over papaverine of a slower onset, longer maintenance and less chance of priapism. Despite these advantages, however, prostaglandin E1 is associated with a significant incidence of penile discomfort.
Prostaglandin E1 is a naturally occurring acidic lipid that is synthesized from fatty acid precursors by most mammalian tissues and has a variety of pharmacologic effects. Human seminal fluid is a rich source of prostaglandins, including PGE1 and PGE2, and the total concentration of prostaglandins in ejaculate has been estimated to be approximately 100-200 mcg/mL. In vitro, alprostadil (PGE1) has been shown to cause dose-dependent smooth muscle relaxation in isolated corpus cavernosum and corpus spongiosum preparations. Additionally, vasodilation has been demonstrated in isolated cavernosal artery segments that were pre-contracted with either noreginephrine or prostaglandin E2xcex1. The vacodilatory effects of alprostadil on the cavernosal arteries and the trabecular smooth muscle of the corpora cavernosa result in rapid arterial inflow and expansion of the lacunar spaces within the corpora. As the expanded corporal sinusoids are compressed against the tunica albuginea, venous outflow through subtunical vessels is impeded and penile rigidity develops. This process is referred to as the corporal veno-occlusive mechanism.
The most notable systemic effects of alprostadil are vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle. Intravenous doses of 1 to 10 micrograms per kilogram of body weight lower blood pressure in mammals by decreasing peripheral resistance. Reflex increases in cardiac output and heart rate may accompany these effects.
Alprostadil is rapidly metabolized locally by enzymatic oxidation of the 15-hydroxyl group to 15-keto-PGE1. The enzyme catalyzing this process has been isolated from many tissues in the lower genitourinary tract including the urethra, prostate, and corpus cavernosum. 15-keto-PGE1 retains little (1-2%) of the biological activity of PGE1. 15-keto-PGE1 is rapidly reduced at the C13-C14 position to form the most abundant metabolite in plasma, 13,14-dihydro,15-keto PGE1 (DKH-PGE1), which is biologically inactive. The majority of DKH-PGE1 is further metabolized to smaller prostaglandin remnants that are cleared primarily by the kidney and liver. Between 60% and 90% of PGE1 has been shown to be metabolized after one pass through the pulmonary capillary beds. Use of the present formulations either alone or in combination with various therapeutic agents overcomes all of these prior art deficiencies.
The drug which causes vasodilation may be any pharmaceutically acceptable substance which causes any vasodilation either directly or indirectly when administered to an animal. In particular, the drug which causes vasodilation may be any drug which is classified, without limitation, in one of the following categories: vasodilators, nitrovasodilators, ACE inhibitors, angiotensin receptor antagonists, phosphodiesterase inhibitors, direct vasodilators, adrenergic receptor antagonists, calcium channel blocking drugs, alpha blockers, beta blockers, lympathomimetics, vitamins, organic nitrates, serotonin receptor -blocking agents, angina blocking agents, other anti-hypertensive agents, cardiac stimulating agents, agents which improve renal, vascular function, sympathomimetic amine and mixtures thereof.
Particularly preferred drugs which cause vasodilation include, without limitation, any of the following: niacin, nitroglycerine, nilatrin hydrochloride, pentoxyphylene, phanoxybenzamine, dichlophenac, papaverine, hydralazine, hydrazaline, hydrochloride, hydrochlorothiazide, sodiumnitroprusside, isoxaprine hydrochloride, epoprostenol sodium, nylidrin hydrochloride, tolazoline hydrochloride, nicotinyl alcohol, phentolamine, phentolamine mesylate, pentolamine hydrochloride, yohimbine, thymoxamine imipramine, verapamil, isoxsuprine, naftidrofuryl, tolazoline, hydroisosorbide, dibenamine, dinitrate, captopril, enalapril, enalaprilat, quinapril, lisinopril, ramipril, losartan, amrinone, milrinone, vesnarinone, nicorandil, prazosin, labetalol, celiprolol, carvedilol, bucindolol, nifedipine dobutamine, minoxidil, nylidrin, and salts thereof, derivatives thereof, precursors thereof and mixtures thereof.
Most preferrably, the drug which causes vasodilation is selected from the group consisting of niacin, nicotinic acid, nicotinic acid precursors, esters of nicotinic acid and mixtures thereof.
Regardless of the route of administration elected, the formulations of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art.
As discussed above, an effective but nontoxic amount of the system is employed in treatment. The dose regimen for administering drugs or treating various conditions, such as pain as described above, is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the severity of the pain, the route of administration and the particular complex or combination of drugs employed. Determination of the proper dose for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum doses of the compound. Thereafter, the dose is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. Generally, amounts of drug may vary from 0.0001% to about 75% by weight of the system when using topically with 0.5 to 5 ml concentrations and preferably in 1 to 3 ml amounts.
The formulations of this invention are particularly useful in the administration of drugs that could be previously administered only by injection.
The transdermal delivery system described herein offers a major alternative especially for those individuals who have a history of undesirable side-effects associated with irritation and/or pain from the injection. Also for those patients who have already suffered damage, the transdermal preparations described herein present a new way of providing effective treatment and relief of painful symptoms.
Female sexual dysfunction is generally caused by vaginal dryness-. Women most susceptible to vaginal dryness include menopausal women, women undergoing radiation therapy, and women suffering from an autoimmune disease. However, vaginal dryness is not limited to such women, and may be caused by numerous factors, many of which may be as yet unidentified. Because female sexual dysfunction has traditionally received significantly less attention than male sexual dysfunction, there is little literature available on the subject.
In many cases vaginal dryness is directly caused by vulvar dystrophy. The vulvar dystrophies are a common group of disorders in which various parts of the vulva atrophy or become dystrophic. While the vulvar dystrophies are common after menopause, they can occur at any time of life, even during childhood. Treatment is often unsatisfactory. See Horrobin, U.S. Pat. No. 5,380,757. Local hygiene and antipruritic ointments and creams may be beneficial but topical preparations containing either glucocorticoids or testosterone, the male sex hormone, are usually required. While these hormone based preparations are often effective, the glucocorticoids when used for long periods carry a serious risk of producing atrophy and thinning of the epithelium, while the testosterone preparations can produce clitoral enlargement or other masculinization.
Vaginal dryness can also be caused by pharmacological influences, for example, as a common side effect of many medications, including diuretics, antiarthritics and antidepressants. Generally, synthetic lubricants or synthetic moisturizers are prescribed for such situations, with limited effectiveness.
The methods and compositions of the present invention contemplate the treatment of female sexual dysfunction in its broadest manifestations. The drug delivery system which the present invention embodies is ideally suited for the topical application of formulations capable of containing an active agent and releasing said agent in a controlled manner to achieve efficacious transdermal drug delivery without the side effects which may accompany the same agent when used with delivery systems disclosed in the prior art. The formulations of the invention may be applied to the surface of the vagina, so that a therapeutically effective amount of the drug for treating vaginal dryness is released in a controlled manner, and thus the drug penetrates the exterior layers of the vagina to relieve said vaginal dryness.
In addition to the negative charged polymers, the transdermal polymer matrix must contain a non-ionic polymer which facilitates in retarding the absorption of the active drug through the skin and delays or slows down in animals natural absorption of the negatively charged polymer.
Without the presence of this component, the active drug would not be delivered transdermally into the site targeted for treatment at levels which are therapeutically effective. In addition to the non-ionic polymers described in this system, these materials are necessary to provide thorough penetration of skin layers including the epidermis, dermis and fatty tissue layers.
Particularly preferred nonionic polymers are cellulose derivatives and particularly those selected from the group consisting of carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose and mixtures thereof. These particular polymers have been found to possess exceptional ability to form sustained release matrix formulations when used in combination with a negative charged polymer. Such polymers are generally employed in amounts of about 0.1% to about 1.5% and preferably about 0.5 to about 1.4%. Amounts above about 1.5% result in the formation of a solid gel when used with the negative charged polymer. Amounts below about 0.1% have not been found suitable to prepare a storage stable product that has sustained drug release.
A particularly preferred HEC concentration is about 0.2% to about 1.0% by weight of the matrix.
A wide variety of other medicaments which may be administered topically may be used in the delivery system according to this invention. These drugs include, without limitation, papaverine hydrochloride, phentolamine mesylate and prostaglandin E1, nicotinic acid, glycerol, propylene glycol, testosterone, testosteronepropionate, glucocorticoids, hydrocortisone, gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA), Yerba Santa extract and mixtures thereof.
One particular criteria of the drug is that they must be solubilized in the polymer matrix solution in order to be topically administered.
The compositions and methods of the present invention are particularly helpful to invidiuals using a medication for preventing or treating hypertension (e.g., an antihypertensive medication) or heart disease, such as organic nitrates. While many currently available therapies for treating erectile dysfunction are contraindicated for individuals on such medications, the present invention is not so contraindicated. For example, oral admistration of sildenafil citrate (viagra(copyright), available from Pfizer) is contraindicated for individuals currently taking organic nitrates, such a nitroglycerine. See xe2x80x9cVIAGRA(copyright) (sildenafil citrate) Tabletsxe2x80x9d, Pfizer Labs, 7 (1998). Thus, the compositions and methods of the present invention may be used by individuals who are currently taking organic nitrates or other drugs which may be used to treat hypertension or heart disease. Moreover, with other currently available therapies which are not specifically contraindicated for use with antihypertensive medication, the dosing of the therapy must be carefully regulated to avoid adverse effects, thus typically preventing a therapeutically effective amount of drug from being delivered to the active site. Accordingly, there is a large group of individuals for whom the present invention may be the only safe and effective therapy.
As noted above, there are numerous causes of male erectile dysfunction. For example, it may be atonic, due to paralysis of the motor nerves without any evidence of lesions to the central nervous system, particularly the spinal cord. Alternatively, it could be psychic, and dependent on a mental problem or instability. Finally, it could be symptomatic, due to some other disorder, such as injury to nerves in the perineal region, by virtue of which the sensory portion of the erection reflex is blocked out. The compositions and methods of the present invention act independently of the particular cause.
Moreover, impotence may be of varying degrees. For example, impotence may be absolute, involving all sexual modalities; or total, affecting all sexual function, though not necessarily libido; or partial, affecting the rigidity or duration of the erection. Whether the cause of impotence is organic, due to structural changes, disease or some demonstrable functional impairment anywhere in the sexual system, psychogenic due to old age or sexual satiation, the result is the same; at least partial inability to engage in sexual activity due to the lack of an adequate erection. The compositions and methods of the present invention act independently of these varying degrees.
The following examples are illustrative of preferred embodiments of the invention and are not to be construed as limiting the invention thereto. All polymer molecular weights are average molecular weights. All percentages are based on the percent by weight of the final delivery system or formulation prepared unless otherwise indicated and all totals equal 100% by weight.

Drug preparations for treating sexual dysfunction