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WO1995003805A1 - Formulation stabilisee - Google Patents

Formulation stabilisee Download PDF

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Publication number
WO1995003805A1
WO1995003805A1 PCT/GB1994/001643 GB9401643W WO9503805A1 WO 1995003805 A1 WO1995003805 A1 WO 1995003805A1 GB 9401643 W GB9401643 W GB 9401643W WO 9503805 A1 WO9503805 A1 WO 9503805A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
acyclovir
tch
topical formulation
herpes
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.)
Ceased
Application number
PCT/GB1994/001643
Other languages
English (en)
Inventor
John David Ludwig
Roy Chetwynd Flanagan, Iv
Jane Muse Partin
Frederick William Gurney
Richard Augustus Winnike
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.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation 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
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Priority to AU72353/94A priority Critical patent/AU7235394A/en
Publication of WO1995003805A1 publication Critical patent/WO1995003805A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0014—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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to a topical pharmaceutical formulation suitable for use in treating viral infections of the skin and mucosa, and in particular to a topical formulation containing 9-(2-hydroxyethoxymethyl)guanine and 2-acetylpyridine 5-[(2- chloroanilino)thiocarbonyl]thiocarbonohydrazone hereinafter referred to as acyclovir and "TCH" respectively.
  • Acyclovir and pharmaceutically acceptable salts and esters thereof are known Jo have antiviral activity against various classes of DNA viruses, in particular herpes viruses such as herpes simplex virus (HSV) and varicella zoster virus (VZV) (U.S. Patent 4, 199, 574).
  • HSV herpes simplex virus
  • VZV varicella zoster virus
  • TCH potentiates the antiviral effects of acyclovir (U.S. Patent 5,021, 437).
  • Topical formulations of TCH with acyclovir suffer from the disadvantage of poor chemical stability of TCH in formulations designed for the solubility characteristics of acyclovir (U.S. Patent 4,963,555). It is accordingly difficult to produce a topical formulation maintaining an optimal ratio of active ingredients which exert their full effects and also to optimize the flux of the compounds into the skin. In addition to ease of release, it is also important that any formulation of a pharmaceutically active compound should be stable for long periods of time, should not lose its potency, should not discolor or form insoluble substances or complexes, and should not be unduly irritating to the skin or mucosa.
  • cream pharmaceutical formulation comprising a dispersed oil phase and a continuous aqueous phase, the formulation containing water, not more than 30% w/w of water-miscible polyhydric alcohol, surfactant, acyclovir or penciclovir, and 2-acetylpyridine-5-[(2- chloroanilino)thiocarbonyl]thiocarbonohydrazone.
  • Such a topical formulation may contain the following components in one or more of the following specified concentrations: 0.075% to 10% w/w acyclovir, 0.045% to 6% w/w TCH, 10% to 30% w/w of a polyhydric alcohol, and/or 30% to 60% w/w water; the percentage concentrations previously specified, and also those specified below, being based on the total weight of the formulation.
  • the formulation' comprises 2% to 8% w/w acyclovir, 1% to 5% w/w (e.g. 1.2% to 4.8%) TCH, 15% to 25% w/w of a polyhydric alcohol, 40% to 60% w/w water together with an oil phase.
  • the formulation comprises 4% to 6% w/w acyclovir, 2.4% to 3.6% w/w TCH, 18% to 23% w/w of a polyhydric alcohol, 45% to 55% w/w water, together with an oil phase.
  • the formulation should most preferably contain about 20% w/w of the polyhydric alcohol and about 50% w/w of water.
  • the most preferred formulation is one which contains 5% w/w acyclovir, 3.15% w/w TCH and 20% w/w polyhydric alcohol (for example propylene glycol).
  • a polyhydric alcohol is an alcohol having two or more hydroxyl groups.
  • Polyhydric alcohols suitable for incorporation into the topical formulation of the present invention include glycols and macrogols such as propylene glycol, butane 1,3-diol, polyethylene glycol, glycerol and glycerol formal, propylene glycol being the preferred polyhydric alcohol.
  • glycols and macrogols such as propylene glycol, butane 1,3-diol, polyethylene glycol, glycerol and glycerol formal, propylene glycol being the preferred polyhydric alcohol.
  • the water used in the formulation is preferably purified water, e.g. according to the standards of the United States Pharmacopoeia.
  • the amount of acyclovir and TCH present in the formulation should be at least sufficient to be antivirally effective and to be non- toxic.
  • a topical formulation with the above-described components satisfies the criteria of adequate stability, maintenance of potency of the combination of active ingredients and minimal irritation to the skin or mucosa. It has advantages over the prior art formulations in maintaining the potency of the acyclovir-TCH combination. As a result, rapid, complete remission of symptoms is achieved by use of such typical formulations in accordance with the invention. It is preferred to use TCH in the crystal form B described below in the topical formulation due to its advantageous properties over crystal form A i.e. the crystal form of TCH obtained in accordance with U.S. Patent No. 5,021,437.
  • TCH exists in multiple unique crystal forms. Each crystal form is characterized by unique X-ray powder diffraction patterns and melting point. The form identified herein as crystal form B is preferred because of its greater thermodynamic and chemical stability in topical formulation compared with form A.
  • Crystal form B of TCH is characterized by the following X-ray diffraction parameters, namely crystal interplanar spacings at 7.83, 7.35, 5.90, 5.73, 4.30, 3.79, 3.69, 3.48, 3.34 and 3.29 angstroms (A), generally with further spacings at 6.37, 5.65, 4J2, 3.94 and 3.39, and by a melting point of 172-176°C, more particularly at 174°C, Additional advantages over crystal form A provided by crystal form B of TCH include reduced tendency to retain water and ease of crystallisation from solution upon cooling. Both properties provide advantages in the production and purification of TCH.
  • substantially free from crystal form A it is meant that the proportion of crystal Form B is higher than that of Form A, preferably the proportion of crystal Form B should be greater than 50%, most preferably greater than 80% and ideally should constitute greater than 95% of the TCH in any product of synthesis of TCH.
  • An additional feature of the invention is provided in the process for the synthesis of crystal Form B of TCH which comprises admixing a solution of TCH in crystal form A in an organic solvent with a lower (e.g. C1. ) alkanol to effect crystallisation of crystal form B of TCH from the said solution.
  • a lower e.g. C1.
  • the initial solution of form A is preferably in a dimethylformamide solvent but other solvents include tetrahydrofuran [and acetonitrile].
  • Examples of the lower alkanol used to effect crystallisation include methanol, ethanol and isopropanol.
  • the initial admixture of the TCH solution with the lower alkanol is preferably conducted at 40°-50°C, advantageously about 45°, followed by cooling for example to 25 °-35° to effect crystallisation.
  • the resulting crystalline product from the above process is advantageously slurried with acetone, and the slurry filtered and dried.
  • This slurrying step removes the lower alkanol, improves the colour of the form B and especially importantly, removes any significant amounts of form A still present in the product.
  • the above formulations according to the invention are essentially emulsions.
  • Such emulsions may be constituted from known ingredients in a known manner.
  • the oil phase may comprise merely an emulsifier also referred to above as a surfactant (otherwise known as an emulgent), it is desirably comprised of a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a more hydrophilic emulsifier is included together with a more lipophilic emulsifier, the combination of which has a stabilizing effect. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with the oil and/or fat make up the so called emulsifying base which forms the oil or dispersed phase of the emulsions in the final formulation.
  • the emulsifying base may contain thickener(s) which may be in the form of a gel or a wax. Many thickening agents improve the stability of the emulsion or may provide additional emulsification.
  • Oil-in-water topical formulations may be formulated in a number of ways, all of which depend primarily on the alignment of the emulsifier and emulsion stabilizer at the " oil/water interface, with the non-polar or lipophilic groups soluble in the oil or dispersed phase and the polar or hydrophilic or lipophilic groups in the aqueous or continuous phase.
  • a more polar hydrophilic emulsifier is selected. This principle has been systematized in the idea of a 'hydrophilic-lipophilic balance' (H.L.B.) Griffen, W. C, J. Soc. Cos. Met.
  • H.L.B. value 8 and 14 is suitable for the formulation of the present invention, preferably about 12.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include poloxamers, polyoxyethylene sorbitan monostearate (polysorbate), sorbitan monostearate, sorbitan monooleate, sodium lauryl sulphate, glycerol monostearate, polyoxyethylene stearate, glycerol monooleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene isohexadecyl ethers, polyoxyethylene sorbitol septaoleate, polyoxyethylene propylene glycol stearate, polyoxyl and most preferable polyoxyethylene stearates (MYRJTM, ICI America) and poly (oxyethylene)monostearyl (or lauryl, cetyl or oleyl) ethers (BRIJTM, ICI America).
  • poloxamers polyoxyethylene sorbitan monostearate (polysorbate), sorbitan monostearate, sorbitan
  • One preferred combination of emulsifiers is BRDTM 721 and BRIJTM 72 in a ratio of 1:10 to 10:1, preferably from 1:5 to 5: 1 most preferably from 1: 1 to 3:1.
  • CTFA-assigned names for BRIJTM 72 and BRIJTM 721 are steareth-2 and steareth-21 respectively.
  • the formulation may contain the emulsifier(s) in an amount of from 1 to 10% w/w, preferably 3 to 8% w/w, most preferably about 5% w/w of the formulation.
  • Optional formulation components include a chelating agent, such as disodium edetate, and fragrances.
  • Penciclovir may optionally replace acyclovir in formulations of the present invention.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of acyclovir in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono-or dibasic alkyl esters such as di-isoadipate, 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 be used. These may be used singly or in combination depending on the properties required, preferable cetyl and stearyl alcohol are not used in combination.
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Light mineral oil is preferred.
  • the formulation may contain oils and/or fats in an amount of from 10-30% w/w, preferably 12- 18% w/w and most preferably 15% w/w.
  • the present invention further provides a method for the preparation of a topical pharmaceutical formulation, as hereinbefore defined, which comprises mixing the combination of acyclovir, TCH, less than 30% w/w polyhydric alcohol, emulsifier(s) and water with the oil phase.
  • acyclovir and TCH may be initially incorporated wholely in the aqueous portion where it may form a solution alone, or a mixed solution/suspension, and then combined with the oil phase to form the emulsion.
  • a part of the aqueous portion may be formulated as an emulsion, and the balance of the water, polyhydric alcohol, acyclovir and TCH added to and dispersed into the emulsion.
  • the acyclovir and TCH may be included in the oil phase prior to emulsification with the aqueous portion.
  • the oil phase and the aqueous phase are combined to form the emulsion to which acyclovir and TCH are added.
  • a method of treating a herpes viral infection for example those referred to below, in a mammal (e.g., a human) which comprises administering to the human an anti- herpes virus effective amount of a topical pharmaceutical formulation as described above.
  • a topical formulation of the present invention may be used in the treatment or prevention of viral infections caused for example by varicella zoster virus and herpes simplex virus, types 1 and 2, which cause diseases such as shingles, chicken pox, cold sores and genital herpes.
  • the formulation should desirably be applied to the affected area of skin from 2 to 6 times daily, preferably from 3 to 4 times. Stability Study
  • Formulations according to invention with various excipient combinations were tested for TCH stability.
  • the decrease of TCH was determined by HPLC.
  • An aqueous cream was prepared from the following ingredients:
  • the oil phase ingredients (mineral oil, BRUTM and stearyl alcohol) were weighed into a beaker and heated with stirring to 65-70°C. Similarly, approximately 90% of the total water, propylene glycol and disodium edetate were heated with stirring to 60-65°C. The two phases were then combined and acyclovir and TCH were added when the temperature reached 50-60°C. The final weight was adjusted to lOOg with water at ca. 50°C. Stirring was resumed until the product cooled to 30- 35°C.
  • An aqueous cream was prepared from the following ingredients:
  • oil phase ingredients (isopropyl myristate, BRIJTM and cetyl alcohol) were weighed into a beaker and heated with stirring to 65-70°C. The remaining ingredients were added as described above for cream formulation A.
  • An aqueous cream was prepared from the following ingredients:
  • Example 2 Crystal Form B of 2-Acetylpyridine 5-[ 2-chloroanilinoV thiocarbonvn thiocarbonohydrazone
  • 2-Acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone, Form A and DMF were combined, stirred and heated to ca. 45°C.
  • the solution was filtered, and methanol (170.3L (134.9kg)) was heated to ca. 45°C and added to the DMF solution.
  • the stirred mixture was slowly cooled to ca. 30°C and optionally seeded with lg of crystal Form B and then cooled to 5°C and held for 1 hour.
  • Crystal Form B of 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbono- hydrazone was placed in a front packed cell, 2 mm depth, and analyzed by powder X-ray diffraction, using a Scintag Powder X-ray Diffractometer with copper K-a radiation source, 1.0 mm divergent slit, 2.0 mm incident scatter slit, scintillation detector with graphite monochromator, 0.1 mm receiving slit, 0.3 mm diffracted scatter slit and a scan rate of 0J degrees/minute (continuous scan mode).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une formulation pharmaceutique topique permet de traiter des infections virales de la peau ou des muqueuses et contient 9-(2-hydroxyéthoxyméthyl)guanine (acyclovir) et 2-acétylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (TCH). Elle comporte une phase huileuse dispersée et une phase aqueuse dispersante contenant de l'eau, 30 % au plus d'alcool polyvalent (en poids de la formulation), un émulsifiant, l'acyclovir et le TCH.
PCT/GB1994/001643 1993-07-30 1994-07-29 Formulation stabilisee Ceased WO1995003805A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72353/94A AU7235394A (en) 1993-07-30 1994-07-29 Stabilized formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939315755A GB9315755D0 (en) 1993-07-30 1993-07-30 Stabilized formulation
GB9315755.0 1993-07-30

Publications (1)

Publication Number Publication Date
WO1995003805A1 true WO1995003805A1 (fr) 1995-02-09

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PCT/GB1994/001643 Ceased WO1995003805A1 (fr) 1993-07-30 1994-07-29 Formulation stabilisee

Country Status (4)

Country Link
AU (1) AU7235394A (fr)
GB (1) GB9315755D0 (fr)
IL (1) IL110511A0 (fr)
WO (1) WO1995003805A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035412A1 (fr) * 1995-05-10 1996-11-14 Hexal Ag Preparation topique d'aciclovir
US6068860A (en) * 1995-02-06 2000-05-30 Astra Aktiebolag Pharmaceutical formulation
US6117857A (en) * 1995-02-06 2000-09-12 Astra Aktiebolag Pharmaceutical composition
US6337324B1 (en) 1995-02-06 2002-01-08 Medivir, Ab Pharmaceutical combination
WO2009115510A1 (fr) * 2008-03-17 2009-09-24 Medivir Ab Formulation antivirale
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963555A (en) * 1980-07-18 1990-10-16 Burroughs Wellcome Co. Formulations of heterocyclic compounds
US5021437A (en) * 1988-06-27 1991-06-04 Burroughs Wellcome Co. 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone compound and salts thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963555A (en) * 1980-07-18 1990-10-16 Burroughs Wellcome Co. Formulations of heterocyclic compounds
US5021437A (en) * 1988-06-27 1991-06-04 Burroughs Wellcome Co. 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone compound and salts thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 119, no. 3, 19 July 1993, Columbus, Ohio, US; abstract no. 20018 *
S.SAFRIN ET AL.: "TOPICAL TREATMENT OF INFECTION WITH ACYCLOVIR-RESISTANT MUCOCUTANEOUS HERPES SIMPLEX VIRUS WITH THE RIBONUCLEOTIDE REDUCTASE INHIBITOR 348U87 IN COMBINATION WITH ACYCLOVIR", ANTIMICRO.AGENTS CHEMOTHER., vol. 37, no. 5, 1993, pages 975 - 979 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6068860A (en) * 1995-02-06 2000-05-30 Astra Aktiebolag Pharmaceutical formulation
US6117857A (en) * 1995-02-06 2000-09-12 Astra Aktiebolag Pharmaceutical composition
US6337324B1 (en) 1995-02-06 2002-01-08 Medivir, Ab Pharmaceutical combination
USRE39264E1 (en) * 1995-02-06 2006-09-05 Medivir Ab Pharmaceutical combination
WO1996035412A1 (fr) * 1995-05-10 1996-11-14 Hexal Ag Preparation topique d'aciclovir
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
WO2009115510A1 (fr) * 2008-03-17 2009-09-24 Medivir Ab Formulation antivirale
JP2009221186A (ja) * 2008-03-17 2009-10-01 Medivir Ab 抗ウイルス製剤
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors

Also Published As

Publication number Publication date
GB9315755D0 (en) 1993-09-15
IL110511A0 (en) 1994-10-21
AU7235394A (en) 1995-02-28

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