Title:  Biodegradable microbicidal vaginal barrier device

United States Patent:  6,572,875

Issued:  June 3, 2003

Inventors:  Neurath; Alexander Robert (New York, NY); Strick; Nathan (Oceanside, NY)

Assignee:  New York Blood Center, Inc. (New York, NY)

Appl. No.:  966924

Filed:  September 28, 2001

An intravaginal bio-erodible microbicidal barrier device. The device comprises (a) at least one micronized compound selected from the group consisting of cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and (b) at least one water soluble or water dispersible cellulose compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose and hydroxypropylethylcellulose. The device is prepared by a combination of foaming, freezing and freeze-drying processes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to bio-erodible microbicidal devices for prevention of STDs based on an acidic polymer which retains antiviral activity at neutral pH and thus does not lose activity in the presence of seminal fluid. Based on applicants, earlier studies, CAP and HPMCP meet these criteria (Neurath, A. R., Strick, N., Li, Y. -Y., Jiang, S., "Design of a `Microbicide` for Prevention of Sexually Transmitted Diseases Using `Inactive` Pharmaceutical Excipients", Biologicals, 27, 11-21, (1999); U.S. Pat. No. 5,985,313).

The present invention involves the use of a micronized compound, such as cellulose acetate phthalate (CAP) and/or hydroxypropylmethylcellulose phthalate (HPMCP).

Some of the properties of CAP as described in the Handbook of Pharmaceutical Excipients are summarized as follows:

Non proprietary Names:

BP: Cellacephate

PhEur: Cellulosi acetas phthalas

USPNF: Cellulose acetate phthalate

Synonyms:

Acetyl phthalyl cellulose; CAP; cellacefate; cellulose acetate hydrogen 1,2-benzenedicarboxylate; cellulose acetate hydrogen phthalate; cellulose acetate monophthalate; cellulose acetophthalate; cellulose acetylphthalate.

Chemical Name and CAS Registry Number:

Cellulose, acetate, 1,2-benzenedicarboxylate [9004-38-0]

Cellulose acetate phthalate is a cellulose in which about half the hydroxyl groups are acetylated and about a quarter are esterified, with one of the two acid groups being phthalic acid. The other acid group is free. See the structural formula below.

Structural Formula: ##STR1##

Functional Category: Coating Agent

Applications in Pharmaceutical Formulation or Technology:

Cellulose acetate phthalate has heretofore been used as an enteric film coating material, or as a matrix binder, for tablets and capsules (Spitael, J., Kinget, R., Naessens, K., "Dissolution Rate of Cellulose Acetate Phthalate and Bronsted catalysis Law", Pharm. Ind., (1980), 42:846-849; Takenaka, H., Kawashima, Y., Lin, S-Y., "Preparation of Enteric-Coated Microcapsules for Tableting by Spray-Drying Technique and in vitro Simulation of Drug Release from the Tablet in GI Tract", J. Pharm. Sci., (1980), 69:1388-1392; Stricker, I., Kulke, H., "Rate of Disintegration and Passage of Enteric-Coated Tablets in Gastrointestinal Tract", Pharm. Ind., (1981), 43:1018-1021; Takenaka, H., Kawashimna, Y., Lin, S-Y, "Polymorphism of Spray-Dried Microencapsulated Sulfamethoxazole with Cellulose Acetate Phthalate and Colloidal Silica Montmorillonite, or Talc", J. Pharm. Sci., (1981), 70:1256-1260; Maharaj, I., Nairn, J. G., Campbell J. B., "Simple Rapid method for the Preparation of Enteric-Coated Microspheres", J. Pharm. Sci., (1984), 73:39-42; Beyger, J. W., Nairn, J. G., "Some Factors Affecting the Microencapsulation of Pharmaceuticals with Cellulose Acetate Phthalate", J. Pharm. Sci., (1988), 75-573-578; Lin, S-Y, Kawashima, Y., "Drug Release from Tablets Containing Cellulose Acetate Phthalate as an Additive or Enteric-Coating Material", Pharm. Res., (1987), 4:70-74; Thoma, K. Hekenmuller, H., "Effect of Film Formers and Plasticizers on Stability of Resistance and Disintegration Behaviour, Part 4: Pharmaceutical-Technological and Analytical Studies of Gastric Juice Resistant Commercial Preparations", Pharmazie, (1987), 42:837-841).

Such coatings resist prolonged contact with the strongly acidic gastric fluid, but soften and swell in the mildly acidic or neutral intestinal environment.

Cellulose acetate phthalate, heretofore used as a pharmaceutical excipient, was commonly applied to solid dosage forms either by coating from organic or aqueous solvent systems, or by direct compression. Concentrations used were 0.5 to 9.0% of the core weight. The addition of plasticizers improves the water resistance of this coating material, and such plasticized films are more effective than when cellulose acetate phthalate is used alone as an adjuvant. Cellulose acetate phthalate is compatible with the following plasticizers: acetylated monoglyceride; butyl phthalylbutyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyethyl glycolate; glycerin; propylene glycol; triacetin; triacetin citrate and tripropionin. Cellulose acetate phthalate has also been used heretofore in combination with other coating agents to control drug release, e.g., ethylcellulose.

Description:

Cellulose acetate phthalate is a hygroscopic, white, free-flowing powder or colorless flakes. It is tasteless and odorless, or may have a slight odor of acetic acid.

Pharmacopeial Specifications:

Typical Properties:

Hygroscopicity: cellulose acetate phthalate is hygroscopic and precautions are necessary to avoid excessive absorption of moisture (Callahan, J. C., Cleary, G. W., Elefant, M., Kaplan, G., Kensler, T., Nash, R. A., "Equilibrium Moisture Content of Pharmaceutical Excipients", Drug Dev. Ind. Pharm., (1982), 8:355-369).

Melting point: 192^oC. Glass transition temperature is 160-170^oC. (Sakellariou, P., Rowe, R. C., White, E. F. T., "The Thermomechanical Properties and Glass Transition Temperatures of Some Cellulose Derivatives used in Film Coating", Int. J. Pharmaceutics, (1985), 27:267-277).

Solubility: practically insoluble in alcohols, chlorinated hydrocarbons, hydrocarbons, and water; soluble in cyclic ethers, esters, ether alcohols, ketones and certain solvent mixtures. Also soluble in certain buffered aqueous solutions at greater than pH 6. The following list shows some of the solvents and solvent mixtures in which cellulose acetate phthalate has a solubility of 1 in 10 parts or more.

Acetone

Acetone: Ethanol (1:1)

Acetone: Methanol (1:1/1:3)

Acetone: Methylene chloride (1:1/1:3)

Acetone: Water (97:3)

Benzene: Methanol (1:1)

Diacetone alcohol

Dioxane

Ethoxyethyl acetate

Ethyl acetate: Ethanol (1:1)

Ethyl acetate: Propan-2-ol (1:1/1:3)

Ethylene glycol monoacetate

Ethyl lactate

Methoxyethyl acetate

.beta.-Methoxyethylene alcohol

Methyl acetate

Methylene chloride: Ethanol (3:1)

Methyl ethyl ketone

Viscosity (dynamic): 50-90 mPas (50-90 cP) for a 15% w/w solution in acetone with a moisture content of 0.4%. This is a good coating solution with a honey-like consistency, but the viscosity is influenced by the purity of the solvent.

Stability and Storage Conditions:

Cellulose acetate phthalate hydrolyzes slowly under prolonged adverse conditions, such as high temperature and humidity, with a resultant increase in free acid content, viscosity and odor of acetic acid. If its moisture content is above about 6% w/w, fairly rapid hydrolysis occurs. However, cellulose acetate phthalate is stable if stored in a well-closed container in a cool, dry place.

Incompatibilities:

Cellulose acetate phthalate is incompatible with ferrous sulfate, ferric chloride, silver nitrate, sodium citrate, aluminum sulfate calcium chloride, mercuric chloride, barium nitrate, basic lead acetate, and strong oxidizing agents such as strong alkalis and acids. It should be noted that one carboxylic acid group of the phthalic acid moiety remains unesterified and free for interactions. Accordingly, incompatibility with acid sensitive drugs may occur (Rawlins E. A., editor, "Bentley's Textbook of Pharmaceutics", London: Bailliere, Tindall and Cox, (1977), 291).

Method of Manufacture:

Cellulose acetate phthalate is produced by reacting the partial acetate ester of cellulose with phthalic anhydride in the presence of a tertiary organic base, such as pyridine.

Safety:

Cellulose acetate phthalate is widely used in oral pharmaceutical products and is generally regarded as a nontoxic material, free of adverse effects.

Results of long-term feeding studies with cellulose acetate phthalate, in rats and dogs, have indicated a low oral toxicity. Rats survived daily feedings of up to 30 in the diet for up to one year without showing a depression in growth. Dogs fed 16 g daily in the diet for one year also remained normal (Hodge, H. C., "The Chronic Toxicity of Cellulose Acetate Phthalate in Rats and Dogs", J. Pharmacol., 80, 250-255, (1944)).

Regulatory Status:

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the United Kingdom.

Pharmacopeias: Aust, Br, Braz, Cz, Eur, Fr, Ger, Gr, Hung, Ind, It, Jon, Mex, Neth, Nord, Port, Swiss and USPNF.

Some of the properties of HPMCP, described in the Handbook of Pharmaceutical Excipients are summarized as follows:

Non proprietary Names: BP: Hypromellose phthalate; PhEur: Methylhydroxypropylcellulosi phthalas and USPNF: Hydroxypropyl-methylcellulose phthalate.

Synonyms: Cellulose phthalate hydroxypropyl methyl ether; HPMCP; 2-hydroxypropylmethylcellulose phthalate; methylhydroxypropylcellulose phthalate.

Chemical Name and CAS Registry Number: Cellulose, hydrogen 1,2-benzenedicarboxylate, 2-hydroxypropyl methyl ether [9050-31-1]

Structural Formula: ##STR2##

Functional Category: Coating Agent.

Applications in Pharmaceutical Formulations or Technology

Hydroxypropylmethylcellulose phthalate has heretofore been widely used in oral pharmaceutical formulations as an enteric coating material for tablets or granules (Ehrhardt, L., Patt, L., Schindler, E., "Optimization of Film Coating Systems", Pharm. Ind., (1973), 35:719-722; Delporte, J. P., Jaminet, F., "Influence of Formulation of Enteric-Coated Tablets on the Bioavailability of the Drug", J. Pharm. Belg., (1976), 31-263-276; Patt, L., Hartmann V., "Solvent Residues Film Forming Agents", Pharm. Ind., (1976), 38:902-906; Stafford, J. W., "Enteric Film Coating Using Completely Aqueous Dissolved Hydroxypropyl Methylcellulose Phthalate Spray Solutions", Drug. Dev Ind. Pharm., (1982), 8:513-530; Thoma, K., Heckenmuller, H., Oschmann, R., "Resistance and Disintegration Behaviour of Gastric Juice Resistant Drugs", Pharmazie, (1987), 42:832-836; Thoma, K., Heckenmuller, H., Oschmann, R., "Impact of Film Formers and Plasticizers on Stability of Resistance and Disintegration Behaviour", Pharmazie, (1987), 42:837-841).

Hydroxypropylmethylcellulose phthalate is insoluble in gastric fluid, but will swell and dissolve rapidly in the upper intestine. Generally, concentrations of 5-10% of hydroxypropylmethylcellulose phthalate were employed with the material being dissolved in either a dichloromethane: ethanol (50:50) or an ethanol: water (80:20) solvent mixture. Hydroxpropylmethylcellulose phthalate can normally be applied to tablets and granules without the addition of a plasticizer or other film formers, using established coating techniques (Rowe, R. C., "Molecular Weight Studies on the Hydroxypropyl Methylcellulose Phthalate (HP55)", Acta. Pharm. Technol., (1982), 28(2):127-130. However, the addition of a small amount of plasticizer or water can avoid film cracking problems; many commonly used plasticizers such as diacetin, triacetin, diethyl and dibutyl phthalate, castor oil, acetyl monoglyceride and polyethylene glycols are compatible with hydroxypropylmethylcellulose phthalate. Tablets coated with hydroxypropylmethylcellulose phthalate disintegrate more rapidly than tablets coated with cellulose acetate phthalate.

Hydroxypropylmethylcellulose phthalate can be applied to tablet surfaces using a dispersion of the micronized hydroxypropylmethylcellulose phthalate powder in an aqueous dispersion of a suitable plasticizer such as triacetin, triethyl citrate or diethyl tartrate along with a wetting agent (Muhammad, N. A., Boisvert, W., Harris, M. R., Weiss, J., "Evaluation of Hydroxypropyl Methylcellulose Phthalate 50 as Film Forming Polymer from Aqueous Dispersion Systems", Drug Dev. Ind. Pharm., (1992), 18:1787-1797).

Hydroxypropylmeclylcellulose phthalate may be used alone or in combination with other soluble or insoluble binders in the preparation of granules with sustained drug release properties; the release rate is pH dependent. Since hydroxypropyl-methylcellulose phthalate is tasteless and insoluble in saliva, it can be used as a coating to mask the unpleasant taste of some tablet formulations.

Description:

Hydroxypropylmethylcellulose phthalate occurs as white to slightly off-white colored free-flowing flakes or as a granular powder. It is odorless or with a slightly acidic odor, and a barely detectable taste.

Typical Properties:

Melting point: 150^oC.

Solubility: practically insoluble in ethanol and water; very slightly soluble in acetone, and toluene; soluble in aqueous alkalis, a mixture of equal volumes of acetone and methanol, and in a mixture of equal volumes of dichloromethane and methanol.

Stability and Storage Conditions:

Hydroxypropylmethylcellulose phthalate is chemically and physically stable at ambient temperature and humidity for 3-4 years, and for 2 to 3 months at 40^oC. and 75% relative humidity (Shin-Etsu Chemical Co., Ltd., Technical Literature: Hydroxypropyl Methylcelluose Phthalate, (1993). Hydroxypropylmethylcellulose phthalate is stable on exposure to UV light for up to 3 months at 25^oC. and 70% relative humidity (Shin-Etsu Chemical Co., Ltd., Technical Literature: Hydroxypropyl-Methylcelluose Phthalate, (1993). In general, hydroxypropylmethylcellulose phthalate is more stable than cellulose acetate phthalate. At ambient storage conditions, hydroxypropylmethylcellulose phthalate is not susceptible to microbial attack.

Incompatibilities:

Incompatible with strong oxidizing agents. Splitting of film coatings has been reported rarely, most notably with coated tablets which contain microcrystalline cellulose and calcium carboxymethylcellulose. Film splitting has also occurred when a mixture of acetone: propan-2-ol or dichloromethane: propan-2-ol has been used as a coating solvent, or when coatings have been applied in conditions of low temperature and humidity. However, film splitting may be avoided by careful selection of the coating solvent used, by using a higher molecular weight grade of polymer (Rowe, R. C., "Molecular Weight Studies on the Hydroxypropyl Methylcellulose Phthalate (HP55), Acta. Pharm. Technol., (1982), 28(2):127-130), or by the addition of a plasticizer, such as acetyl monoglyceride or triacetin. The addition of more than about 10% titanium dioxide to a coating solution of hydroxypropylmethylcellulose phthalate, that is used to produce a colored film coating, may result in coatings with decreased elasticity and gastric fluid resistance (Shin-Etsu Chemical Co., Ltd., Technical Literature: Hydroxypropyl Methylcellulose Phthalate, (1993)).

Method of Manufacture:

Hydroxypropylmethylcellulose acetate phthalate is prepared by the esterification of hydroxypropylmethylcellulose with phthalic anhydride. The degree of methoxy and phthalyl substitution determines the properties of the polymer and in particular the pH at which it dissolves in aqueous media.

Safety:

Hydroxypropylmethylcellulose phthalate has been heretofore widely used, primarily as an enteric coating agent, in oral pharmaceutical formulations. Chronic and acute animal feeding studies on several different species have shown no evidence or teratogenicity or toxicity associated with hydroxypropylmethylcellulose phthalate (Kitagawa, H., Kawana, H., Satoh, T., Fukuda, Y., "Acute and Subacute Toxicities of Hydroxypropyl Methylcellulose Phthalate", Pharmacometrics, (1970), 4(6):1017-1025; Kitagawa, H., Satoh, T., Yokoshima, T., Nanbo, T., "Absorption, Distribution and Excretion of Hydroxypropyl Methylcellulose Phthalate in the Rat", Pharmacometrics, (1971), 5(1):1-4; Ito, R., Toida, S., "Studies on the Teratogenicity of a New Enteric Coating Material, Hydroxypropyl Methylcellulose Phthalate (HPMCP) in Rats and Mice", J. Med. Soc. Toho-Univ., (1972), 19(5):453-461; Kitagawa, H., Yano, H., Fukuda, Y., "Chronic Toxicity of Hydroxypropylmethylcellulose Phthalate in Rats", Pharmacometrics, (1973), 7(5);689-701; Kitagawa, H., Yokoshima, T., Nanbo, T., Hasegawa, M., "Absorption, Distribution, Excretion and Metabolism of ¹⁴ C-hydroxypropyl Methylcellulose Phthalate", Pharmacometrics, (1974), 8(8):1123-1132. Hydroxypropylmethylcellulose phthalate is generally regarded as a nonirritant and nontoxic material.

LD₅₀ (rat, oral): >15 g/kg (Kitagawa et al., Pharmacometrics, (1970), 4(6):1017-1025).

Regulatory Status: included in the FDA Inactive Ingredients Guide (oral capsules and tablets) and included in nonparenteral medicines licensed in the United Kingdom.

Pharmacopeias: Br, Eur, Fr, Gr, It, Jpn, Neth, Port, Swiss and USPNF.

Related Substances: cellulose acetate phthalate; Hydroxypropyl-Methylcellulose.

Hydroxypropylmethylcellulose phthalate can be dissolved in the following solvents:

Acetone: ethanol

Acetone: methanol

Acetone: water (95:5)

Benzene: methanol

Dichloromethane: ethanol

Dichloromethane: methanol

Dioxane

Ethyl acetate: methanol

A particularly preferred micronized preparation for use in the present invention contains micronized CAP and/or micronized HPMCP, or micronized CAP containing other ingredients (a mixture of CAP, a poloxamer and acetylated monoglycerides such as sold by the FMC Corporation under the trade name "AQUATERIC"). A poloxamer is a nonionic polyoxyethylene-polyoxypropylene copolymer.

The chemical name for a poloxamer is .alpha.-hydro-.omega.-hydroxypoly-(oxyethylene) poly(oxypropylene) poly(oxyethylene) block copolymer. The poloxamer polyols are a series of closely related block copolymers of ethylene oxide and propylene oxide conforming to the following formula:

HO(C₂ H₄ O)_a (C₃ H₆ O)_b (C₂ H₄ O)_a H.

The term "micronized" used herein refers to particles having a particle size of less than 35 microns, preferably less than 15 microns, more preferably less than 10 microns and most preferably less than 5 microns.

CAP is commonly used as an enteric film coating material or as a matrix binder for tablets and capsules. Its safety has been extensively studied and it has been shown to be free of adverse effects. Vaginal irritation tests in the rabbit model further confirmed its safety.

The present invention is particularly directed to a soft solid insertable device based on CAP and/or HPHCP. This proved to be difficult to accomplish since CAP is insoluble at low pH, including normal vaginal pH in humans, and solid materials made of CAP are hard, brittle and thus unsuitable for the desired purpose. Furthermore a device generated from CAP would have only a limited surface area available for antiviral/antimicrobial action and would not be likely to be sufficiently effective as a microbicidal device.

To overcome the aforesaid difficulty, applicants employed micronized CAP and/or HPHCP, including a micronized composition, "AQUATERIC", containing 66 to 73 weight a CAP, a polyoxyethylene-polyoxypropylene block copolymer and distilled acetylated monoglycerides (FMC, Philadelphia, Pa.); (Neurath, A. R., Strick, N., Li, Y. -Y., Jiang, S., "Design of a `Microbicide` for Prevention of Sexually Transmitted Diseases Using `Inactive` Pharmaceutical Excipients", Biologicals, 27, 11-21, (1999); U.S. Pat. No. 5,985,313; Gyotoku, T., Aurelian, L., Neurath, A. R., "Cellulose Acetate Phthalate (CAP): An `Inactive` Pharmaceutical Excipient With Antiviral Activity in the Mouse Model of Genital Herpesvirus Infection", Antiviral Chemistry & Chemotherapy, 10, 327-332). This micronized form of CAP was incorporated into sponge-like materials made from other cellulose derivatives, hydroxypropylmethylcellulose ("HPMC") and/or methylcellulose ("MC") by foam generating and freeze-drying processes.

Surprisingly, it was found not only that micronized CAP/"AQUATERIC" can be incorporated into solid foams/sponges generated from HPMC and/or MC, but that such sponges were soft, mechanically resilient and thus ideally suitable as bio-erodible microbicidal vaginal devices. Even more surprisingly, the CAP/"AQUATERIC" not only endows the dried sponges with mechanical resilience, but upon bioerosion initiated by exposure to water, micronized CAP/"AQUATERIC", in its original micronized form, is released from the sponges and thus fully exerts its antiviral/antimicrobial activities. Thus, incorporation of micronized CAP/"AQUATERIC" into the sponges provides not only virucidal and microbicidal properties to the sponges (as described for micronized CAP hereinbefore), but most unexpectedly also provided the sponges with highly desirable mechanical properties, without the need for any ingredients other than the aforementioned cellulose derivatives.

The composition of the foams can be altered by varying the concentrations of CAP and of HPMC and MC and their respective viscosities in such a way that the final properties of the sponges are most desirable. This also depends on the foaming equipment as well as freeze-drying. The optimal conditions can be easily determined by those of ordinary skill in the art. To further scale-up the production of the sponges, equipment for foaming and freeze-drying described in U.S. Pat. No. 5,863,553 (the entire contents of which are hereby incorporated by reference herein) or any alternative equipment available from several different companies internationally can be used.

The "AQUATERIC" composition that is used in the preparation of the CAP-based sponges described hereinabove is a micronized powder, which contains, in addition to CAP (such as approximately 67-70 wt. % CAP), poloxamers and distilled acetylated monoglycerides. The latter two compounds do not contribute to antiviral/virucidal activity. Therefore it is preferable to develop sponges, which contain only a micronized form of CAP, without such other ingredients. Micronization of commercially available CAP granules is not easily feasible in large scale. Similarly, other micronization processes, e.g., an emulsion diffusion process (Quintanar-Guerrero, D., Allemann, E., Fessi, H., and Doelker, E., "Pseudolatex Preparation Using a Novel Emulsion-Diffusion Process Involving Direct Displacement of Partially Water-Miscible Solvents by Distillation", Intl. J. Pharmaceutics, (1999), 188, 155-164) are expensive and cumbersome. The emulsion diffusion process utilizes emulsions generated by a combination of organic solvents (in which CAP has been dissolved) with water; the organic solvent is then removed by evaporation, resulting in a water suspension of micronized CAP. Surprisingly, applicants discovered that this emulsion diffusion process can be combined with foam formation, freezing and freeze-drying, resulting, if an appropriate mold is used for freezing and freeze-drying, in virucidal/microbicidal sponges similar to those described above and prepared from the "AQUATERIC" composition. Surprisingly, the organic solvent does not interfere with the freezing and freeze-drying processes, nor does it adversely affect equipment used in the freeze-drying process.

Claim 1 of 20 Claims

What is claimed is:

1. An intravaginal bio-erodible microbicidal barrier device comprising

(a) at least one micronized compound selected from the group consisting of cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and

(b) at least one water soluble or water dispersible cellulose compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose and hydroxypropylethylcellulose.
 

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