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WO1998010768A1 - Compositions antivirales - Google Patents

Compositions antivirales Download PDF

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Publication number
WO1998010768A1
WO1998010768A1 PCT/EP1997/004945 EP9704945W WO9810768A1 WO 1998010768 A1 WO1998010768 A1 WO 1998010768A1 EP 9704945 W EP9704945 W EP 9704945W WO 9810768 A1 WO9810768 A1 WO 9810768A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
topical pharmaceutical
pharmaceutical formulation
antiviral compound
monoethyl ether
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/EP1997/004945
Other languages
English (en)
Inventor
John Ludwig
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group 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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to AU43842/97A priority Critical patent/AU4384297A/en
Publication of WO1998010768A1 publication Critical patent/WO1998010768A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/33—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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • 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

Definitions

  • This invention relates to a topical pharmaceutical formulation suitable for use in treating virus infections of the skin and mucosa, and in particular it relates to topical formulations containing compounds having antiviral activity, particularly those active against Herpes Simplex Virus, with the exception of aciclovir.
  • viral infections manifest themselves on the skin surface through lesions, rashes, or other forms of skin cell disruption.
  • Particular viral infections are Herpes Simplex Viral infections 1 and 2 which directly cause cold sores and genital sores respectively, and another herpes family virus Varicella Zoster Virus which causes chickenpox and shingles.
  • antiviral compounds have been identified as useful in the systemic treatment of antiviral infections, including but not limited to penciclovir, ganciclovir, idoxuridine, cidofovir and foscamet Many of these compound have undesirable side effects when taken systemically thus making them unsuitable for the treatment of common, non-life threatening, viral infections such as cold sores, genital sores or shingles as described above.
  • An ideal solution is to treat topically the affected areas of the skin either prior or during the attack. This has several advantages such as directing the drug to the affected area and limiting adverse effects to the locality of application.
  • antiviral compounds are difficult to formulate in a suitable cream, gel, ointment or unguent due to, for example, poor solubility and/or do not readily pass through the skin to the affected area.
  • the ability to pass through the skin is particularly important when the antiviral compound is applied during a viral attack but prior to skin cell disruption by a lesion or rash forming.
  • antiviral compound means any compound, except aciclovir, which has a demonstrable effect against any human viral infection.
  • Preferred antiviral compounds are those active against HSV1 or 2 except aciclovir.
  • Particularly preferred compound are selected from penciclovir, famciclovir, ganciclovir, idoxuridine, foscarnet, ribivarin, and cidofovir.
  • Particularly preferred antiviral compounds are penciclovir and cidofovir.
  • any formulation of a pharmaceutically active compound should be stable for long periods of time, should not lose its potency, should not discolour or form insoluble substances or complexes, and also should not be unduly irritating to the skin or mucosa.
  • oil-in-water topical antiviral compound containing pharmaceutical formulations comprising at least 10% by weight of diethylene glycol monoethyl ether have particularly advantageous properties.
  • such formulations exhibit enhanced efficacy together with low irritancy and good physical stability.
  • the present invention accordingly provides an oil-in-water topical pharmaceutical formulation comprising a dispersed oil phase and a continuous aqueous phase comprising water, solubihsed antiviral compound and at least 10% of diethylene glycol monoethyl ether by weight of the formulation.
  • the formulation of the invention contains a maximum of 50% water.
  • Such a topical formulation may contain 0.075% to 10% w/w antiviral compound or a salt or an ester thereof, from 10% to 50% w/w of diethylene glycol monoethyl ether, from 15% to 50% w/w water and an oil phase.
  • antiviral compound should be understood to include also its pharmaceutically acceptable salts and esters unless the context clearly indicates otherwise.
  • the formulation comprises from 0.5% to 10% w/w antiviral compound, from 20% to 40% w/w of diethylene glycol monoethyl ether, from 20% to 40% w/w water together with an oil phase, whilst the most preferred formulation comprises from 1 % to 5% w/w antiviral compound, from 30% to 40% w/w of diethylene glycol monoethyl ether, from 25% to 40% w/w water together with an oil phase.
  • Diethylene glycol monoethyl ether is manufactured by Gatttefosse S.A., 36 Chemin de Genas, b.p. 603, 69804 Saint-Priest Cedex, France, under the tradename TRANSCUTOLTM.
  • Penciclovir or 2-amino-1 ,9-dihydro-9-[4-hydroxy-3(hydroxymethyl)butyl]-6H- purin-6-one may be made in accordance with the procedures described in US 5,075,445.
  • Famciclovir or 2-[2-(2-amino-9H-purin-9-yl-ethyl]-1 ,3-propanediol diacetate, may be made in accordance with the procedures described in M.R. Handen et al, J. Med. Chem. 32, 1738 (1989).
  • Idoxuridine or 1-(2-deoxy-B-D-ribofuranosyl)-5-iodouracil, may be made in accordance with the procedures described in GB 1,024,156.
  • Ganciclovir or 2-amino-1 ,9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl] guanine, may be prepared in accordance with the procedures described in US
  • Foscarnet sodium, or dihydrophosphine carboxylic acid oxide trisodium salt may be prepared in accordance with the procedures described in US 4,215,113.
  • Ribavarin or 1- ⁇ -D-ribofuran-1 H-1 ,2,4-triazole-3-carboxamide, may be prepared in accordance with the procedures described in J.T. Witkowski et al, J. Med. Chem 15, 1150 (1972).
  • Cidofovir or (S)-[[2-(4-amino-2-oxo-1 (2H)-pyrimidinyl)-1 -(hydroxymethyl)ethoxy] methyl]phosphoric acid may be prepared in accordance with the procedures described in US 5,142,051.
  • 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 a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsif ⁇ er(s) with or without stabiliser(s) 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.
  • Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include cetyl alcohol, sodium lauryl sulphate, stearyl alcohol and polyoxyethylene alkyl ethers, such as polyoxyl stearyl ethers, for example steareth 2 and steareth 21.
  • the formulations of the invention may also comprise additional components in the aqueous phase, for example polyhydric alcohols such as propylene glycol.
  • polyhydric alcohols such as propylene glycol.
  • the formulations of the invention comprise from 0 to 30% by weight of propylene glycol.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of most antiviral compounds 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 dialkyl esters such as diisopropyl adipate, 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, the last three being the preferred esters. These may be used singly or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • a preferred formulation according to the invention comprises diethylene glycol monoethyl ether, 30-40% w/w; antiviral compound, approximately 5% w/w; cetyl alcohol 3-10% w/w; stearyl alcohol, 4-10% w/w; propylene glycol, 0-10% w/w; light mineral oil, 8-15% w/w; steareth 21 , 2-5% w/w; steareth 2, l-3% w/w; and purified water to 100% w/w.
  • the formulations of the invention may, if desired, include one or more pharmaceutically acceptable preservatives.
  • preservatives is not essential in the formulations of the invention, which finding represents an advantage of the said formulations.
  • the present invention further provides a method for the preparation of a topical pharmaceutical formulation, as hereinbefore defined, which comprises mixing the combination of antiviral compound, diethylene glycol monoethyl ether and water with the oil phase.
  • the manner of formulating the 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, 1979).
  • the antiviral compound may be initially incorporated entirely in the aqueous portion where it may form a solution alone, or a mixed solution/suspension, and then emulsified with the ointment base.
  • a part of the aqueous portion may be formulated as an emulsion, and the balance of the water, diethylene glycol monoethyl ether and antiviral compound added to and dispersed into the emulsion.
  • the antiviral compound may be included in the emulsifying ointment prior to emulsification with the aqueous portion.
  • a topical formulation of the present invention may be used in the treatment or prevention of viral infections caused for example by Herpes Zoster, Herpes Varicella and Herpes simplex types I and 2, which cause diseases such as shingles, chicken pox, cold sores and genital sores.
  • the formulation should desirably be applied to the affected area of skin from 1 to 6 times daily, preferably from 3 to 5 times.
  • the oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75° C with mixing.
  • Purified water is heated to 65- 70°C and added to the oil phase, maintaining the temperature at 70-75° C , with mixing to form an emulsion.
  • the mixture is maintained at a temperature of
  • TRANSCUTOLTM is weighed into an appropriate container and antiviral compound added with mixing to form a suspension.
  • the antiviral compound suspension is added to the emulsion, rinsing in with a small amount of purified water.
  • the emulsion is homogenised for approximately 5 minutes, then made up to final batch weight with purified water.
  • the resulting cream is cooled to ambient temperature (approximately 30 °C) with continuous mixing and filled into suitable tubes which are then sealed.
  • TRANSCUTOLTM 30.0 antiviral compound 5.0 stearyl alcohol 5.0 cetyl alcohol 4.0 light mineral oil 10.2 brij 721 2.5 brij 72 2.3 propylene glycol 10.0
  • the oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75° C with mixing. Purified water is heated to 70-
  • Example 3 The formulations described in Examples 1 and 2 may alternatively be prepared by the following modified procedure.
  • the oil phase is weighed and heated to 70-75 °C with continuous slow mixing.
  • Purified water is heated to 65-70° C .
  • the purified water is added with propeller agitation to the suspension of aciclovir in TRANSCUTOLTM.
  • the resulting aqueous mixture is heated to 65-70 °C. Whilst maintaining the temperature of the oil phase at 70-75° C, the aqueous phase is slowly added with sweep agitation for at least 5 minutes.
  • the aqueous phase container is rinsed with purified water and the rinsings added to the main batch.
  • the temperature of the batch is maintained at 70-75 °C and the batch is homogenized for at least 5 minutes.
  • the batch is cooled to 30-35 °C with continuous sweep agitation and purified water added to adjust to final batch weight.
  • the batch is mixed until uniform and cooled to 30°C.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation pharmaceutique topique, conçue pour traiter les infections à virus de la peau et des muqueuses, et elle concerne notamment des formulations topiques contenant des composés possédant une activité antivirale, en particulier les composés actifs contre l'herpèsvirus, à l'exception de l'aciclovir. Ces formulations se présentent comme des formulations pharmaceutiques, topiques, huile dans eau, comprenant une phase huile dispersée et une phase eau continue, cette dernière contenant de l'eau, le composé antiviral solubilisé ainsi qu'au moins 10 % du poids de la formulation d'éther de diéthylène glycol et de monoéthyle.
PCT/EP1997/004945 1996-09-11 1997-09-10 Compositions antivirales Ceased WO1998010768A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43842/97A AU4384297A (en) 1996-09-11 1997-09-10 Antiviral compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9618974.1A GB9618974D0 (en) 1996-09-11 1996-09-11 Medicaments
GB9618974.1 1996-09-11

Publications (1)

Publication Number Publication Date
WO1998010768A1 true WO1998010768A1 (fr) 1998-03-19

Family

ID=10799771

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004945 Ceased WO1998010768A1 (fr) 1996-09-11 1997-09-10 Compositions antivirales

Country Status (3)

Country Link
AU (1) AU4384297A (fr)
GB (1) GB9618974D0 (fr)
WO (1) WO1998010768A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051375A1 (fr) * 2001-12-19 2003-06-26 Menarini Ricerche S.P.A. Preparations topiques stabilisees de brivudine
WO2004037263A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Compositions pharmaceutiques de ganciclovir
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
US20190091333A1 (en) * 2017-09-22 2019-03-28 Arcutis, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
JP2023063141A (ja) * 2021-10-22 2023-05-09 花王株式会社 ウイルス不活化剤
US11793796B2 (en) 2017-06-07 2023-10-24 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US11992480B2 (en) 2018-11-16 2024-05-28 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
US12011437B1 (en) 2017-06-07 2024-06-18 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12016848B2 (en) 2017-06-07 2024-06-25 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12042487B2 (en) 2018-11-16 2024-07-23 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
US12042558B2 (en) 2018-06-04 2024-07-23 Arcutis Biotherapeutics, Inc. Method and formulation for improving roflumilast skin penetration lag time
US12144802B2 (en) 2022-09-15 2024-11-19 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast and solvents capable of dissolving high amounts of the drug
US12329751B2 (en) 2020-12-04 2025-06-17 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having antifungal properties
US12453721B2 (en) 2021-12-28 2025-10-28 Arcutis Biotherapeutics, Inc. Topical roflumilast aerosol foams

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0095813A2 (fr) * 1982-06-01 1983-12-07 THE PROCTER & GAMBLE COMPANY Compositions pharmaceutiques topiques pénétrantes contenant la 9-(2-hydroxyéthoxyméthyl)-guanine
WO1995035095A1 (fr) * 1994-06-22 1995-12-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions destinees a l'application de substances actives sur la peau
WO1997034607A1 (fr) * 1996-03-20 1997-09-25 Glaxo Group Limited Formulations d'aciclovir a usage local

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0095813A2 (fr) * 1982-06-01 1983-12-07 THE PROCTER & GAMBLE COMPANY Compositions pharmaceutiques topiques pénétrantes contenant la 9-(2-hydroxyéthoxyméthyl)-guanine
WO1995035095A1 (fr) * 1994-06-22 1995-12-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions destinees a l'application de substances actives sur la peau
WO1997034607A1 (fr) * 1996-03-20 1997-09-25 Glaxo Group Limited Formulations d'aciclovir a usage local

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1316977C (zh) * 2001-12-19 2007-05-23 曼纳里尼里切尔凯有限公司 稳定的溴烯尿苷局部用制剂
WO2003051375A1 (fr) * 2001-12-19 2003-06-26 Menarini Ricerche S.P.A. Preparations topiques stabilisees de brivudine
WO2004037263A1 (fr) * 2002-10-22 2004-05-06 Ranbaxy Laboratories Limited Compositions pharmaceutiques de ganciclovir
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US12310956B2 (en) 2017-06-07 2025-05-27 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
US12336983B2 (en) 2017-06-07 2025-06-24 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US11793796B2 (en) 2017-06-07 2023-10-24 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US11819496B2 (en) 2017-06-07 2023-11-21 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US12220409B2 (en) 2017-06-07 2025-02-11 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12005051B2 (en) 2017-06-07 2024-06-11 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
US12005052B2 (en) 2017-06-07 2024-06-11 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US12011437B1 (en) 2017-06-07 2024-06-18 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12016848B2 (en) 2017-06-07 2024-06-25 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12257242B2 (en) 2017-06-07 2025-03-25 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US11534493B2 (en) * 2017-09-22 2022-12-27 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
US20190091333A1 (en) * 2017-09-22 2019-03-28 Arcutis, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
US12042558B2 (en) 2018-06-04 2024-07-23 Arcutis Biotherapeutics, Inc. Method and formulation for improving roflumilast skin penetration lag time
US12042487B2 (en) 2018-11-16 2024-07-23 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
US11992480B2 (en) 2018-11-16 2024-05-28 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
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JP2023063141A (ja) * 2021-10-22 2023-05-09 花王株式会社 ウイルス不活化剤
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