WO1996031207A1 - Formule de gel au podofilox - Google Patents
Formule de gel au podofilox Download PDFInfo
- Publication number
- WO1996031207A1 WO1996031207A1 PCT/NO1996/000079 NO9600079W WO9631207A1 WO 1996031207 A1 WO1996031207 A1 WO 1996031207A1 NO 9600079 W NO9600079 W NO 9600079W WO 9631207 A1 WO9631207 A1 WO 9631207A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- podofilox
- gel
- gel composition
- pharmaceutical gel
- composition
- Prior art date
Links
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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Definitions
- This invention relates to the manufacture and use of pharmaceutical compositions. More particularly, this invention relates to the manufacture of certain gel compositions that contain as their active
- Genital warts or Condyloma acumina tum , is a sexually-transmitted cutaneous viral disease resulting from infection with a strain of Human Papilloma Virus (HPV). This disease is approaching epidemic
- podofilox The drug of choice for treating genital warts, and related conditions such as perianal and mucous membrane warts, is podofilox.
- Podofilox the chemical name of which is 5, 8, 8a, 9-tetrahydro-9-hydroxy-5- (3,4,5-trimethoxyphenyl) furo[3',4':6,7]naphtho [2, 3,d]- 1, 3-dioxol-6 (5aH) -one, can be purified from the plant families Coniferae and Berberidaceae (e.g. species of Juniperus and Podophyllum) or can be chemically synthesized.
- Coniferae and Berberidaceae e.g. species of Juniperus and Podophyllum
- Podofilox is currently formulated for use in the treatment of genital warts as an alcohol solution.
- CONDYLOX ® 0.5% solution a product of Oclassen Pharmaceuticals, Inc., is a formulation for topical administration in which each milliliter of solution contains 5 mg of podofilox in a vehicle containing lactic acid and sodium lactate in alcohol 95% USP.
- Liquid formulations are more easily and likely to be swallowed, for instance by children. Alcohol
- Podofilox is a potent toxin
- Liquid formulations are generally applied using an applicator or absorbent medium such as tissue, a "cotton ball", or a small stick with an absorbent tip.
- Non-liquid topical formulations can be applied with the fingertip, a procedure that is less wasteful of product.
- fingertip self- application is easier to accomplish on areas of the body that cannot easily be seen by the patient as opposed to application by means of an applicator stick or rod medium. The more controlled the application, of course, the less potential safety concern by contamination of uninfected skin.
- podofilox readily undergoes a structural epimerization to form degradation products such as picropodophyllotoxin, with concomitant loss of activity. This reaction, while not totally absent, is much slower under moderately acidic conditions
- a lactic acid/sodium lactate buffer system maintains the solution at a pH of about 2.5 to 4.0
- gelling systems are polymeric esters or ethers, which are subject to hydrolysis at low pH.
- Typical gelling agents used to make pharmaceutical gels include the Carbomers, which are acidic
- the gelling agent In addition to the need with respect to podofilox of a gelling agent that can be used at a pH in the range 2-5, the gelling agent would have to be physically stable (e.g. resist hydrolysis) and would have to be able to gel in alcohol.
- the present invention is based upon the realization that
- appropriate gelling agents would have to meet these three criteria: ability to gel in alcohol; ability to gel at pH 2-5; and physical stability (no hydrolysis).
- hydrophilic cellulose derivatives such as hydroxypropylcellulose will enable the preparation of stable topical gel formulations of podofilox. Accordingly, the present invention relates to methods for the manufacture of pharmaceutical compositions comprising solutions of podofilox in alcohol or similar solvents which are thickened by means of hydrophilic cellulose derivatives, as well as to the compositions themselves and to methods for the treatment of topical lesions resulting from infection with the Human Papilloma Virus as common, plantar, 'or genital warts and related diseases by applying these pharmaceutical compositions.
- Figure 1 depicts the efficacy for the treatment of genital warts of a podofilox gel in accordance with the invention as compared to a podofilox solution providing the same dosage level.
- Figure 2 depicts the same data as Figure 1, separated by male and from female patients.
- Figure 3 depicts the degree of local effects of a podofilox gel in accordance with the invention as compared to a podofilox solution providing the same dosage level.
- Figure 4 depicts the same data as Figure 3, as derived from male and from female patients.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a solution of podofilox in a lower alkanol, aldehyde, and/or ketone, wherein the solution is thickened with a hydrophilic cellulose.
- the amount of podofilox that may be incorporated into the gels in accordance with the present invention is any amount that is great enough to destroy or at least slow the growth of genital warts but not so great as to cause unacceptable collateral damage to uninvolved skin of the host.
- effective relative amounts of podofilox in accordance with the present invention generally range from about 0.1 to 5 percent by weight. Currently, 0.5%
- formulations of podofilox are preferred for formulations of podofilox
- the lower alkanol in which the podofilox may be dissolved in accordance with the present invention is any alkanol of up to 8 carbon atoms. Alkanols having from 1 to 4 carbon atoms are preferred, and ethanol is most preferred, since it is generally recognized as safe for use on humans. Alternatively to or in addition to lower alkanols, other pharmaceutically solvents such as low molecular weight aldehydes and ketones may also be used as solvents in accordance with the invention.
- Evaporation of the alkanol, aldehyde, and/or ketone solvent enhances penetration of the active ingredient into the lesion. Penetration can be made to occur still faster by the inclusion in the
- Evaporation of the solvent also serves to increase the relative concentration of the active ingredient at the site of application.
- the hydrophilic cellulose that can be used in accordance with the present invention is any cellulose derivative that is able to thicken the podofilox alcohol solution into a gel.
- the hydrophilic cellulose that can be used in accordance with the present invention is any cellulose derivative that is able to thicken the podofilox alcohol solution into a gel.
- Hydroxymethylcellulose hydroxyethylcellulose
- hydroxypropylcellulose, and carboxymethylcellulose are illustrative of hydrophilic cellulose derivatives that may be used in accordance with the present invention.
- the hydrophilic cellulose derivative that is currently most preferred is hydroxypropylcellulose.
- the gelling agents would typically be used in concentrations sufficient to prepare gels of suitable viscosity and physical characteristics.
- the relative amount of gelling agent used in accordance with the present invention may range from about 1% to about 10%, and is preferably from 3 to 6%, with the precise amount being selected to provide a gel viscosity in the range of about 5000 to about 100,000 centipoise. It has been found that gels made with approximately 4% hydroxypropylcellulose give excellent results.
- Gels in accordance with the present invention are sufficiently viscous to provide positional stability on the skin but can still be easily dispensed from a suitable container and spread on the lesion.
- the hydrophilic cellulose is selected and used in an amount that provides a gel which dries readily to a non-tacky state but which is sufficiently water- soluble to permit facile clean-up from the skin of the patient.
- Any pharmaceutically acceptable buffer system that can maintain the gel in accordance with the present invention at a pH in the range of
- the buffer system will generally comprise a mixture of an acid and its salt.
- Organic mono- and polycarboxylic acids such as acetic lactic, citric, tartaric, fumaric, and so on, as well as common mineral acids such as hydrochloric,
- counterions such as those formed by sodium, potassium, ammonia, or non-toxic organic amines. It is currently preferred that the pH be maintained in the range 3-3.5 by a buffer system comprising lactic acid and sodium lactate.
- antioxidants such as butylated
- hydroxytoluene may be used to protect the podofilox from oxidation.
- formulation vehicles may be added.
- glycerin can be used to. promote dispersion of the hydrophilic cellulose.
- Pigments such as titanium dioxide may be added to provide desirable visual attributes to the gels.
- Podofilox as used hereinbelow may be obtained from pHarma-medica, a-s, of Herlev, Denmark.
- the hydroxypropylcellulose as used hereinbelow may be obtained as "Klucel” from Aqualon Company of Hopewell, Virginia. The remaining ingredients as used
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- n-propanol was added to a suitable tared mixing vessel with a variable speed agitator.
- the podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved.
- the lactic acid and sodium lactate were added to a reserve container and heated to about 50°C.
- a slurry was made with the hydroxypropylcellulose and glycerin.
- the heated buffers were used to aid in the formation of the slurry.
- the hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated
- hydroxytoluene in alcohol More of the n-propanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- n-butanol was added to a suitable tared mixing vessel with a variable speed agitator.
- the podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved.
- the lactic acid and sodium lactate were added to a reserve container and heated to about 50°C.
- a slurry was made with the hydroxypropylcellulose and glycerin.
- the heated buffers were used to aid in the formation of the slurry.
- the hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated
- hydroxytoluene in alcohol More of the n-butanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- variable speed agitator The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved.
- the lactic acid and sodium lactate were added to a reserve container and heated to about 50°C.
- a slurry was made with the hydroxypropylcellulose and glycerin.
- the heated buffers were used to aid in the formation of the slurry.
- the hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following com onents:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- variable speed agitator The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved.
- the lactic acid and sodium lactate were added to a reserve container and heated to about 50oC.
- a slurry was made with the hydroxypropylcellulose and glycerin.
- the heated buffers were used to aid in the formation of the slurry.
- the hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- a clear colorless podofilox gel in accordance with the present invention was manufactured as
- variable speed agitator The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved.
- the lactic acid and sodium lactate were added to a reserve container and heated to about 50°C.
- a slurry was made with the hydroxypropylcellulose and glycerin.
- the heated buffers were used to aid in the formation of the slurry.
- the hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components:
- An opaque white podofilox gel in accordance with the present invention was manufactured as follows: Approximately two-thirds of the alcohol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. A portion of the heated buffers were used to aid in the formation of the slurry. The titanium dioxide was added to the remainder of the heated buffers and dissolved.
- the titanium dioxide/buffer mixture was added to the hydroxypropylcellulose/glycerin slurry, and the resulting buffer mixture was added to the mixing vessel containing the podofilox and butylated hydroxytoluene in alcohol. More.of the alcohol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes. Comparative Examples
- a gel base was prepared using 5% ethylcellulose The ethylcellulose went into solution but the
- a gel base was prepared from the following components:
- a gel base was prepared from the following components:
- the resultant gel retained a sticky feel when dried.
- podofilox gel One thousand gram lots of podofilox gel were prepared from the following components by the
- podofilox solution One thousand gram lots of podofilox solution were prepared from the following components:
- the primary efficacy variable is the number of the treated warts at each visit.
- the efficacy data is graphically depicted in Figure 1.
- Figure 1 demonstrates that from the first week of the study through its conclusion at 12 weeks, the efficacy was better for those patients whose genital warts were treated with the gel as compared to those whose genital warts were treated with the solution.
- the gel produced up to an 80% reduction in the number of warts compared to up to a 60% reduction with the solution.
- Figure 2 subsets these data by gender, and shows that positive response to the gel formulation was
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- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
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Abstract
La présente invention concerne des compositions de gels pharmaceutiques qui comprennent l'agent antimitotique et antiviral qu'est le podofilox en quantité efficace sur le plan thérapeutique, en vue de produire au moins un ralentissement de la croissance de verrues dans un hôte, un solvant comprenant un(e) alcanol, aldéhyde, cétone inférieur(e)s, ou un mélange de ces composés, en quantité suffisante pour former une solution avec le podofilox, et une cellulose hydrophile en quantité efficace pour épaissir la solution et former un gel. L'invention concerne aussi des méthodes de traitement des verrues, plus spécialement les verrues génitales et les cas analogues, au moyen des compositions en question.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU53490/96A AU5349096A (en) | 1995-04-05 | 1996-04-03 | Podofilox gel formulation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41740695A | 1995-04-05 | 1995-04-05 | |
US08/417,406 | 1995-04-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996031207A1 true WO1996031207A1 (fr) | 1996-10-10 |
Family
ID=23653899
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NO1996/000079 WO1996031207A1 (fr) | 1995-04-05 | 1996-04-03 | Formule de gel au podofilox |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR001807A1 (fr) |
AU (1) | AU5349096A (fr) |
IL (1) | IL117801A0 (fr) |
WO (1) | WO1996031207A1 (fr) |
ZA (1) | ZA962728B (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9592188B2 (en) | 2014-05-22 | 2017-03-14 | Yansong Liu | Method of treating or reducing the severity of dermatological conditions |
BE1026494B1 (fr) * | 2018-12-26 | 2020-02-18 | Dermax Sa | Procede ameliore de production de gel de podofilox |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0119852A1 (fr) * | 1983-03-18 | 1984-09-26 | Pharma-medica a-s | Préparation à base de podophyllotoxine pour le traitement de verrues génitales |
US5084579A (en) * | 1988-09-19 | 1992-01-28 | L'oreal | Benzofuran compounds |
US5173289A (en) * | 1988-01-20 | 1992-12-22 | Centre International De Recherches Dermatologiques (C.I.R.D.) | Aromatic esters and thioesters, a process for their preparation and their use in human or veterinary medicine and in cosmetic compositions |
-
1996
- 1996-04-02 IL IL11780196A patent/IL117801A0/xx unknown
- 1996-04-03 AU AU53490/96A patent/AU5349096A/en not_active Abandoned
- 1996-04-03 WO PCT/NO1996/000079 patent/WO1996031207A1/fr active Application Filing
- 1996-04-04 ZA ZA962728A patent/ZA962728B/xx unknown
- 1996-04-08 AR AR33608296A patent/AR001807A1/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0119852A1 (fr) * | 1983-03-18 | 1984-09-26 | Pharma-medica a-s | Préparation à base de podophyllotoxine pour le traitement de verrues génitales |
US5173289A (en) * | 1988-01-20 | 1992-12-22 | Centre International De Recherches Dermatologiques (C.I.R.D.) | Aromatic esters and thioesters, a process for their preparation and their use in human or veterinary medicine and in cosmetic compositions |
US5084579A (en) * | 1988-09-19 | 1992-01-28 | L'oreal | Benzofuran compounds |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9592188B2 (en) | 2014-05-22 | 2017-03-14 | Yansong Liu | Method of treating or reducing the severity of dermatological conditions |
BE1026494B1 (fr) * | 2018-12-26 | 2020-02-18 | Dermax Sa | Procede ameliore de production de gel de podofilox |
Also Published As
Publication number | Publication date |
---|---|
AR001807A1 (es) | 1997-12-10 |
ZA962728B (en) | 1996-10-09 |
AU5349096A (en) | 1996-10-23 |
IL117801A0 (en) | 1996-08-04 |
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