WO2006010589A2 - Mousse en gel post-moussant - Google Patents
Mousse en gel post-moussant Download PDFInfo
- Publication number
- WO2006010589A2 WO2006010589A2 PCT/EP2005/008108 EP2005008108W WO2006010589A2 WO 2006010589 A2 WO2006010589 A2 WO 2006010589A2 EP 2005008108 W EP2005008108 W EP 2005008108W WO 2006010589 A2 WO2006010589 A2 WO 2006010589A2
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- WIPO (PCT)
- Prior art keywords
- drugs
- formulations according
- treatment
- amount
- pharmacologically active
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- AOXRBFRFYPMWLR-XGXHKTLJSA-N ethylestrenol Chemical compound C1CC2=CCCC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](CC)(O)[C@@]1(C)CC2 AOXRBFRFYPMWLR-XGXHKTLJSA-N 0.000 description 1
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- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
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- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
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- 210000000214 mouth Anatomy 0.000 description 1
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- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
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- 239000001272 nitrous oxide Substances 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
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- 238000004806 packaging method and process Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
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- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
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- 239000008213 purified water Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
Definitions
- This invention relates to formulations adapted particularly for insertion of a pharmacologically active agent into a body cavity for systemic treatment or prophylaxis of a medical condition in the patient being treated, or for localised treatment or prophylaxis of the mucosal surface of the cavity of the patient into which the formulation is inserted. More particularly this invention relates to pharmaceutical compositions suited to the treatment or prophylaxis of systemic medical conditions, or of localised medical conditions of the mucosa. The invention is also concerned with methods of treatment of bacterial or fungal mucosal infections.
- the mucosal surfaces of the human body represent a relatively unexplored mechanism by which pharmacologically active agents may be delivered to patients requiring either local or systemic prophylactic or medical treatment.
- Post-foaming gel mousses have been used for some time in the toiletry industry, especially for shaving gels such as for example in US 5,186,857 (RAMIREZ et al), US 5,500,211 (GEORGE et al), and US 6,165,456 (BARNET et al).
- the main foaming agents (propellants) used in these products are n-pentane and/or iso-pentane. These allow the product to be dispensed as a non-expanded gel, which then expands slowly to a foam, mainly from the warming effect of skin temperature. Neither of these materials is approved for use in pharmaceutical products.
- the pharmaceutically-acceptable propellants all have too high a pressure to be used in a post- foaming gel, as they cause rapid expansion of the gel, causing the pain or discomfort referred to previously.
- CFC propellants eg combinations of CFCs 11, 12 and 114, but these are now prohibited because of their effect on the ozone layer.
- a formulation suited to the delivery of pharmacologically active agent into the body cavity of a patient to be treated said formulation comprising foaming agents, surfactants, thickeners and optionally when required, vapour pressure reducers.
- the foaming agent is a pharmaceutically acceptable propellant and more preferably, the foaming agent is n-butane.
- the formulation is a gel at room temperature, until upon application, it expands into a mousse or foam at a rate so as to not cause discomfort, and to a degree sufficient to adequately coat the mucosal surface of the body cavity.
- the term “comprising” shall be taken to mean that the subject matter to which it relates may contain additional components, features, characteristics, ingredients or combinations thereof which are not specifically mentioned, and shall not be taken so as to exclude additional components, features, characteristics, ingredients or combinations thereof which are not specifically mentioned.
- the term “pharmacologically active agent” shall be taken to mean any chemical substance listed in any pharmacopoeia for prophylactic or therapeutic treatment of a medical condition or a potential medical condition in a patient.
- the formulations of the invention may be used to deliver contraceptives, lubricants, anti fungal and anti bacterial substances, and other known pharmacologically active agents for localised use, but may also be used for delivery of immunogenic substances such as vaccines or for other known medical substances for local or systemic treatment of, for example, wounds, ulcers and psoriasis. Any medical application in which mucosal treatment or mucosal delivery of an active agent is advantageous will be suitably treated by formulations of the invention incorporating pharmacologically active agents.
- Suitable pharmacologically active agents may include anabolic steroids such as methyltestosterone, ethyloestrenol; NSAID drugs (non-steroidal anti ⁇ inflammatory drugs), such as asprin, ibuprofen, indomethacin, ketoprofen; sedatives and hypnotics such as diazepam, lorazepam, oxazepam; the barbiturates, including pentobarbitone, phenobarbitone, chloral hydrate; thyroid hormones such as thyroxine and liothyronine; vaccines such as cholera, diphtheria, hepatitis A, hepatitis B, H.
- steroids such as methyltestosterone, ethyloestrenol
- NSAID drugs non-steroidal anti ⁇ inflammatory drugs
- sedatives and hypnotics such as diazepam, lorazepam, oxazepam
- influenzae type B influenza, measles, mumps, polio, rubella, pertussis, tenanus, typhoid, yellow fever; anti ⁇ migraines such as ergotamine, methysergide, propranolol, anti-oestrogens such as tamoxifen and clomiphene; beta-blockers such as alprenolol, propranolol; corticosteroids such as betmethasone, budesonide, cortisone, hydrocortisone, prednisolone, clobetasol; female sex hormones such as oestradiol, medroxyprogesterone; fertility drugs such as clomiphene; immune suppressants such as cyclosporin, methotrexate; inhibitors of bone reabsorption such as etridronate; anti-emetics (nausea and vomiting) such as metroclopramide, promethazine; anti-endometrio
- a pharmaceutical composition suited to insertion into the body cavity of a patient to be treated, said composition comprising one or more pharmacologically active agents, foaming agents, surfactants, thickeners and optionally, when required, vapour pressure reducers.
- the foaming agent is a pharmaceutically acceptable propellant and more preferably, the foaming agent is n-butane.
- the composition is a gel at room temperature, until upon application, it expands into a mousse or foam at a rate so as to not cause discomfort, and to a degree sufficient to adequately coat the mucosal surface of the body cavity.
- compositions of the invention may be suited to treatment of medical conditions in the vaginal, anal, ear, oral and nasal cavities, wound cavities/fissures, or may be suited to treatment of systemic medical conditions via these cavities. They may also be suited to the delivery of immunogenic substances which may pass into the patients circulation for the purposes of generating antibodies via the mucosal lining of the site of application. Suitable pharmacologically active agents for delivery in this embodiment of the invention are those previously listed.
- Thickeners used according to the invention may be selected from the group comprising povidone, cellulose gums such as sodium carmellose, xanthan gum and other pharmaceutically acceptable thickeners, or combinations thereof. These thickeners may also act as stabilisers for the composition and help it slowly develop from a gel to a foam after application to the body cavity of interest, as well as improving the mucoadhesive qualities of the formulation.
- Surfactants desirably included in the formulations and compositions of the invention so as to assist in formation of the foam, the emulsification of the vapour pressure reducers, and the solubilisation of the active agents may include but are not limited to nonoxinol, polysorbate, glyceryl stearate, glycol stearate, sorbitan esters, polyoxylated stearates, polyoxylated castor oil, macrogol alkyl ethers such as macrogol lauryl ether, and other pharmaceutically acceptable surfactants or combinations of the foregoing.
- Suitable foaming agents may be selected from but are not limited to hydrocarbons such as n-butane, chlorofluorocarbons, hydrofluorocarbons, dimethyl ether, nitrogen, nitrous oxide and carbon dioxide. These foaming agents must not cause excessively rapid expansion of the foam in the body cavity of a patient since discomfort and/or pain will result.
- the foaming agents may be combined with oily substances such as for example caprylic/capric triglycerides which act as vapour pressure reducers or solvents.
- oily substances such as for example caprylic/capric triglycerides which act as vapour pressure reducers or solvents.
- vapour pressure reducers or solvents may be used alone or in combination.
- compositions may also include other excipients such as for example pH buffers, solvents, carriers, diluents and preservatives.
- pH buffers may include citrates, phosphates or acetates, or other pharmaceutically acceptable buffers.
- Suitable preservatives may include benzyl alcohol or parabens, and other pharmaceutically acceptable preservatives.
- Suitable carriers and diluents may include purified water.
- compositions and formulations of the invention are desirably packaged as a metered aerosol, a single-shot vial, or as a two-compartmental system such as a "bag-in-can" type aerosol product.
- Packaging in a pressurized container is desirable to mitigate against premature expansion of the mousse.
- compositions according to the invention preferred ranges of the components of the compositions are as follows.
- Thickeners may be present in an amount of 0.1 - 30% m/m, more preferably 1.0 - 15% m/m.
- Surfactants may be present in an amount of 1.0 - 60% m/m, more preferably 4.0 - 40% m/m.
- pH buffers may be present in an amount of 0 - 10% m/m, more preferably 0.1 - 2.0% m/m.
- Oily substances may be present in an amount of 1.0 - 30% m/m, more preferably 5.0 - 20% m/m.
- Preservatives may be present in an amount of 0.01 - 5.0% m/m, more preferably 0.2 - 2.0% m/m.
- the pharmacologically active agent may be present in varying amounts depending on the profile of the drug, the condition to be treated and whether or not localised or systemic treatment is required. In the case of anti-fungal agents, amounts may vary from 0.05 - 20% m/m.
- the bulk of the compositions according to the invention is made up by a suitable solvent such as water lower alcohols and glycols and combinations thereof which may be present in amounts of 10 - 95% m/m, more preferably 40 - 80% m/m.
- a method of treatment of a fungal or bacterial infection of the vagina comprising administering to a patient requiring such treatment an effective amount of a pharmaceutical composition according to the invention wherein the pharmacologically active agent is an anti fungal or anti bacterial agent.
- the pharmacologically active agent is selected from the group consisting of clotrimazole, ketoconazole, miconazole and terconazole.
- This formulation is simply prepared by blending all ingredients into the water using an overhead stirrer. Sodium CMC is premixed with part of the nonoxinol 9. Mixing is continued for approximately 30 minutes. The pH and viscosity are adjusted to suit application to a body cavity as a gel.
- compositions including a pharmacologically active agent according to the invention are as follows:
- compositions and formulations exemplified in accordance with the invention may be rendered suitable for use by the addition of approximately 10% n-butane in one preferred embodiment.
- This example compares the retention and distribution of the post foaming gel mousse according the invention with the widely used anti-fungal Canesten® Cream.
- a and B upper right and left quadrants
- Region E is a sanitary pad collection means external of the vagina of a patient being treated. Healthy, non-pregnant pre-menopausal women gave informed consent. Following an induction health screen, the subjects were studied twice, with the test or control formulation administered in random order 28 days apart. Canesten cream (Bayer Australia) was radio-labelled (by continuous mixing) with 99mm TcDTPA, so that the administered dose was 4MBq in the standard 6g applicator. 99mm TcDTPA was added to 0.5ml of a formulation according to the invention prior to pressurisation and production of a foaming gel, so that 4MBq was incorporated in the test dose. Preparations were weighed and counted before, and after administration to determine accurately the amount administered. A standard was produced, so that gamma-camera, and gamma counter results could be cross-calibrated. All counts were decay corrected.
- Simultaneous anterior and posterior images were obtained 15 minutes after dosing and at 15 minute intervals for the first hour. Hourly images were then obtained for 7 hours, with a final image at 24 hours. Geometric mean counts were recorded for the whole vagina, and four arbitrary quadrants, and for an extra- vaginal region. Tomography was obtained at 1, 4 and 7 hours. A sanitary pad was changed after each imaging event, and counted to determine the activity lost. The difference between the sum of the activity seen on the gamma camera, and counted on the sanitary pad, and that administered was the activity not accounted for.
- FIGS. 2 and 3 show the distribution in a typical subject of the Gel Mousse according to the invention and the Canesten Cream within the vagina over 24 hours.
- Figure 2 indicates virtually all the dose is equally distributed between the two upper quadrants, and slowly and evenly diffuses into the lower quadrants.
- the Canesten Cream according to figure 3 is unevenly located in upper quadrant A, with minimal amounts in the other upper quadrant. It also diffuses into the lower quadrants, but remains unevenly distributed in the right hand side of the vagina. This is confirmed by the scintigrams, figures 4 and 5.
- the scintigrams are in pairs, anterior and posterior.
- the uneven distribution of the cream mentioned above is clearly seen in these images.
- Some areas of the vaginal epithelium are not in contact with the cream.
- the Gel Mousse has expanded fairly rapidly to fill the vaginal cavity, and has given extensive coverage of the epithelium and good retention within the vaginal cavity.
- the formulations and compositions developed in accordance with the invention result in a product which has a delayed expansion upon application so as to minimise discomfort to a patient.
- the product may be prepared and stored under pressure as a gel but upon delivery assumes the form of a foam or mousse. Good coverage of the epithelium of the cavity being treated is demonstrably achieved.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Reproductive Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Gynecology & Obstetrics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004904260A AU2004904260A0 (en) | 2004-07-29 | Post foaming gel mousse | |
AU20004/904260 | 2004-07-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006010589A2 true WO2006010589A2 (fr) | 2006-02-02 |
WO2006010589A3 WO2006010589A3 (fr) | 2006-08-03 |
Family
ID=35672370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/008108 WO2006010589A2 (fr) | 2004-07-29 | 2005-07-26 | Mousse en gel post-moussant |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2006010589A2 (fr) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2479891A (en) * | 2010-04-27 | 2011-11-02 | David Chamberlain | Foaming solution to provide acoustic dampening in the ear canal |
US8343945B2 (en) | 2007-12-07 | 2013-01-01 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
US8795635B2 (en) | 2006-11-14 | 2014-08-05 | Foamix Ltd. | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US9622947B2 (en) | 2002-10-25 | 2017-04-18 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
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