Lyophilized pharmaceutical compositions for vaginal delivery

• US 11,026,883 B2
• Filed: 10/13/2017
• Issued: 06/08/2021
• Est. Priority Date: 10/13/2016
• Status: Active Grant

• Current Assignee: Catalent U.K. Swindon Zydis Limited (Catalent, Inc.)
• Original Assignee: Catalent U.K. Swindon Zydis Limited (Catalent, Inc.)
• Inventors: Masto, Emilie, Garrett, Lisa, Barrat, Niamh, Wong, Yik Teng, McLaughlin, Rosaleen Theresa, Banbury, Susan Gerrard
• Primary Examiner(s): Mercier, Melissa S
• Application Number:
  US16/341,808
• Publication Number:
  US 20190314274A1
• Time in Patent Office: 1,334 Days
• Field of Search: None
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2036 Silicones; Polysiloxanes
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin
• CPC Class Codes: 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
• CPC Class Codes: A61P 15/04 for inducing labour or abortion; Uterotonics
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals

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

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.

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

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

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

5. 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.

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

7. 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.

8. 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.

9. 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.

10. 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.

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

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

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

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

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

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

21. 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.