# US 11,026,883 B2 · Lyophilized pharmaceutical compositions for vaginal delivery

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- Number: US 11,026,883 B2
- Document ID: US11026883B2
- Status: Granted
- Kind: B2
- Application number: 16/341,808
- Filed: 2017-10-13
- Published: 2019-10-17
- Granted: 2021-06-08
- Earliest claimed: 2016-10-13
- Assignees: Catalent U.K. Swindon Zydis Limited
- Applicants: Catalent U.K. Swindon Zydis Limited
- Inventors: Emilie Masto; Lisa Garrett; Niamh Barrat; Yik Teng Wong; Rosaleen Theresa McLaughlin; Susan Gerrard Banbury
- Web page: https://patentgrep.com/patent/US11026883B2

## CPC

- A61K 9/0036: {Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/0034: {Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2036: {Silicones; Polysiloxanes}
- A61K 9/205: {Polysaccharides, e.g. alginate, gums; Cyclodextrin}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/2063: {Proteins, e.g. gelatin}
- A61K 9/2072: {characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms (A61K9/0004, A61K9/0056, A61K9/0065 take precedence)}
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61P 15/04: for inducing labour or abortion; Uterotonics
- A61P 15/16: Masculine contraceptives
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein is a solid lyophilized vaginal dosage form that can have an effective amount of at least one active ingredient, a crystalline structure forming agent in an amount of about 5 wt. % to about 40 wt. %, based on the total weight of the lyophilized dosage form, and at least one polymeric mucoadhesive matrix forming agent. The dosage form can have a pH of about 4.0 to 5.0, and can disintegrate within 120 seconds after being contacted with a vaginal mucosa. A method of delivering an active ingredient to the vaginal mucosa using the disclosed solid dosage form is also described.

## Claims

### Claim 1

A solid lyophilized vaginal dosage form including:
a) an effective amount of at least one active ingredient;
b) a crystalline structure forming agent in an amount of 12.5 wt. % to 25 wt. %, based on the total weight of the lyophilized dosage form; and
c) at least one polymeric mucoadhesive matrix forming agent;
wherein the dosage form disintegrates within 120 seconds after being contacted with a vaginal mucosa.

### Claim 2 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form disintegrates within 90 seconds of being contacted with the vaginal mucosa.

### Claim 3 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the mucoadhesive matrix forming agent comprises at least one fish gelatin.

### Claim 4 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the mucoadhesive matrix forming agent comprises at least one bovine gelatin.

### Claim 5 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the mucoadhesive matrix forming agent comprises 1 to 60 wt. % based on the total weight of the lyophilized dosage form.

### Claim 6 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the crystalline structure forming agent comprises a sugar or sugar alcohol.

### Claim 7 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the crystalline structure forming agent comprises a structure forming agent selected from mannitol, xylitol, saccharose, glucose, lactose, fructose, dextrose, galactose, trehalose, cyclodextrin and any combination thereof.

### Claim 8 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form further comprises at least one lubricant selected from colloidal silicon dioxide, simethicone, and polyoxypropylene-polyoxyethylene copolymer.

### Claim 9 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form comprises a mucoadhesive matrix forming agent selected from chitosan, methylcellulose and hydroxyethylcellulose and hydroxypropyl methylcellulose polymers.

### Claim 10 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form comprises a mucoadhesive matrix forming agent selected from gelling or non-gelling gelatins, hydrolysed or non-hydrolysed gelatin, povidone, starch, modified starches, dextrins, soy, wheat and psyllium seed proteins, chitosan, dextrans, polysaccharides, polypeptide/protein or polysaccharide complexes, gelatin-acacia complexes, methylcellulose, carboxymethyl cellulose, thiolated carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxylpropyl methylcellulose and methylhydroxyethyl cellulose, agaros, hyaluronic acid, carrageenans, pectins, alginates, polyacrylic acids, cross-linked poly(acrylic acids), polycarbophil, polyacrylates, methacrylic acid polymers, polyvinyl alcohol, polyvinyl pyrrolidone, ethylhexyacrylate, other thiolated polymers, gums and any combination thereof.

### Claim 11 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form further comprises a pH modifier.

### Claim 12 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form has a porosity of at least 60%.

### Claim 13 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form has a porosity of from 60% to under 85%.

### Claim 14 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form has a physical robustness sufficient to resist breakage with handling and insertion of the dosage form into the vaginal cavity.

### Claim 15 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the dosage form has a tablet strength greater than 10N to less than 100N as measured by the Peak Load to Fracture.

### Claim 16 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the active ingredient comprises up to 60 wt. % based on the total weight of the lyophilized dosage form.

### Claim 17 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the active ingredient is selected from the group consisting of acyclovir, fluconazole, progesterone, nonoxylenol-9, terbutaline, lidocaine, testosterone, dinoprostone, lactobacillus, estrogen, naphthalene2-sulfonate, butoconazole, clindamycin nitrate/phosphate, neomycine sulfate, polymyxin sulfate, nystatin, clotrimazole, dextrin sulphate, glyminox, miconazole nitrate, benzalkonium chloride, sodium lauryl sulphate, tenofovir, danazol, acriflavine, leuprorelin acetate, metronidazole, benzydamine hydrochloride, chloramphenicol, oxybutynin, ethinyl estradiol, insulin, calcitonin, and salts, esters, hydrates, and solvates of any of the foregoing active ingredients that possess the same activity as the active ingredient, vaccine antigens of HIV, HPV, Chlamydia, Heptatits B, gonococcus and combinations thereof.

### Claim 18 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the active ingredient is selected from the group consisting of antibacterial agents, antifungal agents, antiprotozoal agents, antiviral agents, labor-inducing agents, spermicidal agents, prostaglandins, steroids and microbicides, proteins/peptides, vaccine antigens and combinations thereof.

### Claim 19 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, further comprising silicon dioxide.

### Claim 20 (depends on 1)

The solid lyophilized vaginal dosage form of claim 1, wherein the crystalline structure forming agent comprises mannitol.

### Claim 21 (depends on 1)

A method of delivering an active ingredient to a vaginal cavity comprising the step of contacting the solid lyophilized vaginal dosage form as claimed in claim 1 with the vaginal mucosa.