CA2113080C - Topical composition containing penciclovir - Google Patents

Topical composition containing penciclovir

Info

Publication number
CA2113080C
CA2113080C CA 2113080 CA2113080A CA2113080C CA 2113080 C CA2113080 C CA 2113080C CA 2113080 CA2113080 CA 2113080 CA 2113080 A CA2113080 A CA 2113080A CA 2113080 C CA2113080 C CA 2113080C
Authority
CA
Grant status
Grant
Patent type
Prior art keywords
penciclovir
water
propylene glycol
pharmaceutical formulation
phase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA 2113080
Other languages
French (fr)
Other versions
CA2113080A1 (en )
Inventor
Alan John Goodall
Hazel-Ann Griffiths
Joshua Oduro-Yeboah
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis International Pharmaceutical Ltd
Original Assignee
Novartis International Pharmaceutical Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Abstract

An oil-in-water or an aqueous topical pharmaceutical formulation for the treatment of virus infections of the skin or muco-sa, comprising at least 30 % propylene glycol, at least 0.75 % penciclovir and 0.5 to 1 % Cetomacrogol 1000.

Description

TOPICAl. COMPOSITION CONTAINING PENCICLOYIR
This invention relates to a topical pharmaceutical formulation suitable for use in the treatment of virus infections of the skin and mucosa.
EP=A-141927 (Beecham Group p.l.c.) discloses fihe compound 9-(4-hydroxy-3-hydroxymethylbut-1=yl)guanine, known as BR,L 39n123 or pen~clovir, its salts and esters thereof and its use. in the treatment of herpesvirus infections. Topical administration is disclosed as a suitable route. Hereinafter, references to. penciclovir include salts and estxrs thereof.
It is important with a topical formulation of an antiherpesvirus drug that the quantity of drug released from the formulation is sufficient to exert a significant antiviral effect and that the drug rapidly reaches its site of action within the skin.
Rapid penetration is important, since inmost cases, major virus induced epidermal pathology occurs within the~first 24 hours post infection. Once the infection is established aid the stratum corneum has been eroded, the rapid ingress of host resistant.factors could make chemotherapy of questionable value.
WO 91/12187 Beecham Group p.l.c.) discloses an oiI-in-water topical pharmaceutical formulation or an aqueous formulation for the treatment .
of virus infections of the skin or mucosa, comprising at least 30~v of propylene glycol and solubilised penciclovir.
A new antiviral topical formulation has now. been discovered, having improved properties as compared with conventional formulations.
Accordingly, the present invention provides an ail-in-water topical pharmaceutical formulation or an aqueous formulation for the treatment of virus infections of the skin or mucosa, comprising at least 30% of propylene glycol, at least 0.?5% penciclovir and 0.5 to I°7o Cetoima.crogolTM, 1000.
Such a topical formulation may contain up to 10% w/w penciclovi.r and WO 93/00905 ~ ~ ~ ~ ~~- ~ ~ PCT/GB92/01208 from 30% to 60% w/w of propylene glycol and from 15% wlw water (up to 50% when there is an oil phase).
In a preferred aspect the formulation comprises from 0.75 or 1% to 10%
w/w penciclovir, from 30% to 50% w/w of propylene glycol, from 20% w/w water (up to 40%, when there is an oil phase). Examples of suitable formulations comprise from 2% to 5% w/w penciclovir, from 35% to 45%
wlw of propylene glycol, from 25% to 40% w/w water together with an oil phase. A preferred formulation, however, comprises 0.75% or 1% to 5%
penciclovir. The formulation should preferably contain about 40% w/w of propylene glycol.
The amount of penciclovir present in the formulation should be at least su~cient to maintain an antivirally effective concentration at the site of infection between applications without showing signs of toxicity. The optimum concentration of penciclovir will depend on its solubility in the vehicle. Penciclovir may be included in the formulation at a level exceeding its solubility in order to provide a reservoir and to maintain the antiviral agent at a saturated concentration within the vehicle. One suitable amount in the above preferred formulation is up to 10% w/w, such as 2-8%, for example 5%. A preferred amount is less than 5%, such as 0.5 - 2%, for example 1%.
The water used in the formulation is preferably purified water, purified that is by distillation by means of ion exchange or other appropriate method, such as reverse osmosis.
The oil phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it is desirably comprised of a mixture of at least one emulsifier with one or more excipients including oils, fats and/or waxes, together with optional film formers and stabilisers as well as thickening and bodying agents.
Preferably, as explained in more detail below, an additional hydrophilic emulsifier is included together with a lipohilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifiers) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so called emulsifying ointment base which forms the oil dispersed phase of the emulsions.
Oil-in-water topical formulations may be formulated in a number of ways, all of which depend primarily on the alignment of the emulgent or emulsifying agent and emulsion stabiliser at the oiUwater interface, with the non-polar or lipophilic groups soluble in the oil phase and thE: polar or hydrophilic groups in the aqueous or continuous phase. Thus the more polar hydrophilic eiinulgents result in oil-in-water emulsions. This principle has been systemised in the idea of a 'hydrophilic-lipophilic balance' (H.L:B.) Griffen, W. C. J. Soc. Cosmet. Chem.,1954, 5, 249 and the various~emulgents have been allocated H.L.B. numbers from which their behaviour with constituents of the aqueous and oiI phases ('to which are applied theoretical required H.L.B. figures) may be predicted.
The emulsion stabiliser for use in the formulation of the present iinvention is Cetomacrogot 1000 (Polyethylene Glycol 1000 Monocetyl Ether) present in a proportion of 0.5 to 1% by weight, such as 0.7 to 1.0~, preferably 0.9%
to 1.0%, the optimum concentration being 0.94%.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Lipophilic substances with relatively high melting points, such as beeswax, partial glycerides of capric and caprylic acids, or silicone oily white soft paraffin, andfor liquid para~n or other mineral or vegetable oils are suitable. Straight ~or branched chain, mono- or dibasic alkyl esters such as di-isopropylladipate, isocetyl stearate; propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl~
palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol~CAP may also be used.
As well as creams, the aqueousloil-in-water formulation may be a lotion;
skin paint, gel, spray, aerosol, liniment or gel stick, which are formulated as known in the art, for example as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, the British Pharmacopoeia, USP twenty-first revision (USP XXI) (1984), distributed by Mack Publishing Company.

WO 93/00905 PCI'/GB92/01208 .~. ~ ~i ~ a ~ -4-The product may or may not be sterile, with adequate preservative capacity for single or multi-dose purposes.
In this description, the following terms are employed:
Aerosol - Pharmaceutical aerosols are products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system. The term 'aerosol' has been used to refer to the fine mist of spray that is emitted from a pressurized container containing an active ingredient and a propellant.
However, the term has been broadly applied to include all self contained pressurized products, some of which deliver foams or semisolid fluids.
Accordingly, unless indicated otherwise, a reference herein to an aerosol formulation of the present invention should be understood to include pharmaceutical compositions for topical use comprising a pharmaceutically acceptable carrier which includes a propellant, said compositions being adapted for use in a pressurized container that dispenses the composition as a spray, foam or semisolid liquid.
An aerosol generally comprises a container, a propellant, a concentrate containing the active ingredient, a valve (which may be a metered valve), and an actuator. The nature of these components determines characteristics such as delivery rate, foam density, and fluid viscosity.
Aerosols may be two-phase (gas and liquid) or three-phase (gas, liquid, and solid or liquid formulations. A two-phase formulation consists of a solution of active ingredients in liquidified propellant and the vaporized propellant. The solvent may be the propellant or a mixture of the propellant and co-solvents such as alcohol and polyethylene glycols which are often used to enhance the solubility of the active ingredients.
Three-phase formulations consist of a suspension or emulsion of the active ingredients) in addition to the vaporized propellants. A suspension consists of the active ingredients) dispersed in the propellant system with the aid of suitable excipients such as wetting agents and/or solid carriers such as talc or colloidal silicas. A foam formulation is generally an emulsion containing one or more active ingredients, surfactants, aqueous or nonaqueous liquids, and the propellants. If the propellant is in the internal (discontinuous) phase (i.e., of the oil-in-water type), a stable foam vu ~~_s~uuyu~ t~Otic~tsy~iu~?ur is discharged, and if the propellant is in the external (continuous) phase (i.e., of the water-in-oil type), a spray or a quick-breaking foam is discharged. [See The United States Pharmacopeia, XXI ('USP') at 1334].
Gels - Gels are semisolid systems consisting either of suspensions made up of small inorganic particles or of large organic molecules interpenetrated by a liquid. Where the gel consists of a network of small discrete particles, the gel is classified as a two-phase system. In a two-phase gel, if the particle size of the dispersed phase is relatively large, the gel is sometimes referred to as a magma. Both gels and magmas may be thixotropic, forming semisolids on standing and becoming liquid on agitation.
Single-phase gels consist of organic macromolecules uniformly distributed throughout a liquid so that no apparent boundaries east between the dispersed macromolecules and the liquid. Single-phase gels may be made from synthetic macromolecules (e.g. Car~omer)* or from natural gums (e.g. Tragacanth). The latter preparations are also called mucilages.
Although single-phase gels are commonly aqueous, alcohols and oils may also be used as the continuous phase. For example, mineral oil can be combined with a polyethylene resin to form a gel which may be used as an oleaginous ointment base (see USP, supra at 1336].
Lotion - Preferred lotions include fluid o~r thixotropic emulsions intended for external application to the body. These lotions are emulsions of the oil-in-water type stabilized by a surface-active agent. They may separate or stratify on long standing, and should be well shaken before each use.
Adequate preservation against microbial contamination is required [see USP, supra at 133?].
Gel stick - The definition of gel sticks set forth in Harry's Cosmeticology, 6th Edition, at 740.
'Excipients that are italicised in this discussion are classified as pharmacopoeial preparations (USP or BP).

WO 93/00906 F'(-f /(;B92/0120H

Liniment - Liniments are solutions or mixtures of various substances in oil, alcoholic solutions of soap, or, emulsions, as in the present invention.
They are intended for external application and are usually applied with friction and rubbing of skin, the oil or soap base providing for ease of application and massage.
Spray - As used in this description, spray formulations are aqueous solutions of various drugs which are applied topically from a container having a spray means (e.g., an atomizer or nebulizer).
The present invention further provides a method for the preparation of a topical pharmaceutical formulation, as hereinbefore defined, which comprises mixing the combination of penciclovir, propylene glycol, Cetomacrogol 1000 and water, optionally with oil phase.
The manner of formulating an emulsion will of course vary according to the amount and nature of the constituents, but nevertheless follows known techniques in emulsion technology (see The Pharmaceutical Codex, London, The Pharmaceutical Press, 19 7 9). In a preferred method penciclovir may be included in the oil phase prior to emulsification with the aqueous portion. Alternatively the penciclovir may be initially incorporated wholly in the aqueous portion where it may form a solution alone, or mixed solutionlsuspension, and then emulsified with the ointment base, or a part of the aqueous portion may be formulated as an emulsion, and the balance of the water, propylene glycol and penciclovir added to and dispersed into the emulsion. In using these procedures, it is preferable to heat the aqueous portion and the ointment base to about 40 to 80oC, preferably 50 to 70oC, prior to emulsification which may be achieved by vigorous agitation using for example a standard laboratory mixer. Finer dispersions of the oil phase may be obtained by homogenising or milling in a colloidal mill.
A topical formulation of the present invention may be used in the treatment or prevention of viral infections caused by herpesviruses such as herpes simplex types 1 and 2 and varicella-zoster virus.
The formulation should be applied to the affected area 2 to 6 times daily, WO 93/00905 ~ ~ ~ ~ ~ ~ ~ PCT/GB92/01208 _7_ preferably 2 or 3 times.
The following examples illustrate the invention.
CREAMS CONTAINING PROPYLENE GLYCOL
% w/w Example 1 Aqueous phase Cetomacrogol 1000 0.90 Propylene glycol 40.00 Purified Water 26.74 Oil phase Cetostearyl alcohol 7.41 Liquid paraffin 5.70 BRL 39123 (penciclovir) 5.00 White soft paraffin 14.25 Example 2 Aqueous Phase Cetomacrogol 1000 0.90 Propylene Glycol 40.00 Purified Water 25.30 Oil Phase Cetostearyl Alcohol 7.80 Liquid Paraffin 6.00 White Soft Paraffin 15.00 BRL 39123 (penciclovir) 5.00 2~~~~c~
% w/w Ezample 3 Aqueous Phase Cetomacrogol 1000 0.85 Propylene Glycol 40.00 Purified Water 26.79 Oil Phase Cetostearyl Alcohol 7.41 Liquid Paraffin 5.70 White Soft Paraffin 14.25 BRL 39123 (penciclovir) 5.00 Ezample 4 Aqueous Phase Cetomacrogol 1000 0.94 Propylene Glycol 41.79 Purified Water 27.94 Oil Phase Cetostearyl Alcohol 7.74 Liquid Paraffin 5.96 BRL 39123 (penciclovir) 0.75 White Soft Paraffin 14.88 % w/w Example 5 Aqueous Phase Cetomacrogol 1000 0.94 Propylene Glycol 41.68 Purified Water 27.87 Oil Phase Cetostearyl Alcohol 7.72 Liquid Paraffin 5.94 B1ZL 39123 (penciclovir) 1.00 White Soft Paraffin 14.85 Example 6 Aqueous Phase Cetomacrogol 1000 0.93 Propylene Glycol 41.26 Purified Water 27.58 Oil Phase Cetostearyl Alcohol 7.64 Liquid Paraffin 5.88 BItL 39123 (penciclovir) 2.00 White Soft Paraffin 14.71

Claims (9)

1. An oil-in-water or an aqueous topical pharmaceutical formulation for the treatment of virus infections of the skin or mucosa, comprising at least 30%
w/w propylene glycol, at least 0.75% w/w penciclovir and 0.5 to 1 % w/w Cetomacrogol .TM. 1000.
2. The pharmaceutical formulation according to claim 1 containing from up to loo w/w penciclovir, 30 to 60% w/w propylene glycol and at least 15% w/w water.
3. The pharmaceutical formulation according to claim 2 comprising from 30 to 50% w/w propylene glycol and at least 20% w/w water.
4. The pharmaceutical formulation according to claim 3 comprising 0.75 or 1 to 5% w/w penciclovir, 35 to 45% w/w propylene glycol and 25 to 40% w/w water together with an oil phase.
5. The pharmaceutical formulation according to any one of claims 1 to 4 comprising 1% w/w penciclovir.
6. The pharmaceutical formulation according to any one of claims 1 to 5 comprising 0.9 to 1.0% w/w Cetomacrogol .TM. 1000.
7. A method for the preparation of a pharmaceutical formulation according to claim 1, 2, 3, 5 or 6, which method comprises admixing the combination of penciclovir, propylene glycol, Cetomacrogol .TM. 1000 and water, optionally with an oil phase.
8. A method for the preparation of the pharmaceutical formulation according to claim 4, which method comprises admixing the combination of penciclovir, propylene glycol, Cetomacrogol .TM. 1000, water and oil phase.
9. Use of a pharmaceutical formulation according to any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of viral infections.
CA 2113080 1991-07-11 1992-07-03 Topical composition containing penciclovir Expired - Lifetime CA2113080C (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
GB9114939A GB9114939D0 (en) 1991-07-11 1991-07-11 Pharmaceutical formulation
GB9114939.3 1991-07-11
PCT/GB1992/001208 WO1993000905A1 (en) 1991-07-11 1992-07-03 Tropical composition containing penciclovir

Publications (2)

Publication Number Publication Date
CA2113080A1 true CA2113080A1 (en) 1993-01-21
CA2113080C true CA2113080C (en) 2003-02-25

Family

ID=10698164

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2113080 Expired - Lifetime CA2113080C (en) 1991-07-11 1992-07-03 Topical composition containing penciclovir

Country Status (9)

Country Link
EP (1) EP0593562B1 (en)
JP (1) JP2865867B2 (en)
KR (1) KR100245016B1 (en)
CA (1) CA2113080C (en)
DE (2) DE69228686T2 (en)
DK (1) DK0593562T3 (en)
ES (1) ES2128353T3 (en)
GB (1) GB9114939D0 (en)
WO (1) WO1993000905A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6124304A (en) * 1993-10-05 2000-09-26 Smithkline Beecham Plc Penciclovir for the treatment of zoster associated pain
GB9326177D0 (en) * 1993-12-22 1994-02-23 Smithkline Beecham Plc Pharmaceuticals
CN1235547A (en) * 1996-10-31 1999-11-17 里科达蒂化学药物公司 Antiherpetic pharmaceutical compositions containing acyclovir for topical applicators
US7223387B2 (en) 1998-11-18 2007-05-29 Medivir Ab Antiviral formulations comprising propylene glycol and an isopropyl alkanoic acid ester
GB9828620D0 (en) * 1998-12-23 1999-02-17 Glaxo Group Ltd Medicaments

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8917959D0 (en) * 1989-08-05 1989-09-20 Beecham Group Plc Pharmaceutical formulation
GB9001886D0 (en) * 1990-01-26 1990-03-28 Beecham Group Plc Pharmaceutical formulation

Also Published As

Publication number Publication date Type
GB9114939D0 (en) 1991-08-28 grant
JP2865867B2 (en) 1999-03-08 grant
DK0593562T3 (en) 1999-09-27 grant
DE69228686T2 (en) 1999-09-09 grant
WO1993000905A1 (en) 1993-01-21 application
CA2113080A1 (en) 1993-01-21 application
EP0593562A1 (en) 1994-04-27 application
JPH06508845A (en) 1994-10-06 application
EP0593562B1 (en) 1999-03-17 grant
DE69228686D1 (en) 1999-04-22 grant
DK593562T3 (en) grant
KR100245016B1 (en) 2000-03-02 grant
ES2128353T3 (en) 1999-05-16 grant

Similar Documents

Publication Publication Date Title
US5894019A (en) Topically applied pharmaceutical composition, method of preparing it and its use
US4956173A (en) Composition and use of ademetionine against ageing of the skin
US20050069566A1 (en) Foam carrier containing amphiphilic copolymeric gelling agent
US20090180970A1 (en) Foamable composition combining a polar solvent and a hydrophobic carrier
US20040241099A1 (en) Foamable pharmaceutical compositions and methods for treating a disorder
US20060233721A1 (en) Foam containing unique oil globules
US8709385B2 (en) Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses
US6214318B1 (en) Aerosol ointment compositions for topical use
US5314685A (en) Anhydrous formulations for administering lipophilic agents
US4719239A (en) Pharmaceutical multicomponent systems and method of preparing same
US5720948A (en) Non-ionic surfactant emulsion vehicles and their use for deposition of drug into and across skin
US20050244342A1 (en) Moisturizing foam containing lanolin
US20130028850A1 (en) Topical tetracycline compositions
US5990100A (en) Composition and method for treatment of psoriasis
US20080234239A1 (en) Topical composition
US6486124B2 (en) Cyclosporin compositions and process therefor
US8435498B2 (en) Penetrating pharmaceutical foam
US4731384A (en) Etofenamate formulation
US20080206161A1 (en) Quiescent foamable compositions, steroids, kits and uses thereof
US20130189191A1 (en) Carriers, Formulations, Methods For Formulating Unstable Active Agents For External Application And Uses Thereof
US8114385B2 (en) Oleaginous pharmaceutical and cosmetic foam
US20080138293A1 (en) Cosmetic and pharmaceutical foam
US20060204526A1 (en) Emulsive composition containing Dapsone
US5681849A (en) Pharmaceutical composition for topical applications
US6121314A (en) Pharmaceutical composition

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry