MXPA01006490A - Aciclovir compositions containing dimethicone - Google Patents
Aciclovir compositions containing dimethiconeInfo
- Publication number
- MXPA01006490A MXPA01006490A MXPA/A/2001/006490A MXPA01006490A MXPA01006490A MX PA01006490 A MXPA01006490 A MX PA01006490A MX PA01006490 A MXPA01006490 A MX PA01006490A MX PA01006490 A MXPA01006490 A MX PA01006490A
- Authority
- MX
- Mexico
- Prior art keywords
- water
- formulation
- topical
- dimethicone
- acyclovir
- Prior art date
Links
- MKUXAQIIEYXACX-UHFFFAOYSA-N acyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960004150 aciclovir Drugs 0.000 title claims abstract description 54
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 title claims abstract description 49
- 235000013870 dimethyl polysiloxane Nutrition 0.000 title claims abstract description 47
- 239000004205 dimethyl polysiloxane Substances 0.000 title claims abstract description 46
- 229940008099 dimethicone Drugs 0.000 title claims abstract description 45
- UQEAIHBTYFGYIE-UHFFFAOYSA-N Hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 title claims abstract 13
- 239000000203 mixture Substances 0.000 title claims description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 230000000699 topical Effects 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 239000012071 phase Substances 0.000 claims abstract description 17
- 239000008346 aqueous phase Substances 0.000 claims abstract description 15
- 229940023040 Acyclovir Drugs 0.000 claims description 51
- 238000009472 formulation Methods 0.000 claims description 37
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 26
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 7
- 206010047461 Viral infection Diseases 0.000 claims description 6
- 208000001756 Virus Disease Diseases 0.000 claims description 6
- 230000017613 viral reproduction Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 241001529453 unidentified herpesvirus Species 0.000 claims description 2
- CXQXSVUQTKDNFP-UHFFFAOYSA-N Simethicone Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 34
- 206010015150 Erythema Diseases 0.000 description 24
- 231100000321 erythema Toxicity 0.000 description 24
- 239000006071 cream Substances 0.000 description 16
- 201000009910 diseases by infectious agent Diseases 0.000 description 16
- 239000008213 purified water Substances 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 12
- 229960004063 Propylene glycol Drugs 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 229940107931 Zovirax Drugs 0.000 description 9
- 239000003995 emulsifying agent Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 8
- 210000003491 Skin Anatomy 0.000 description 7
- 230000000840 anti-viral Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 206010037888 Rash pustular Diseases 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 230000003902 lesions Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- -1 polydimethylsiloxane Polymers 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 229940044476 Poloxamer 407 Drugs 0.000 description 4
- 229940082500 cetostearyl alcohol Drugs 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000019271 petrolatum Nutrition 0.000 description 4
- 229920001992 poloxamer 407 Polymers 0.000 description 4
- 241000700198 Cavia Species 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 208000009889 Herpes Simplex Diseases 0.000 description 3
- 206010022114 Injury Diseases 0.000 description 3
- 206010033733 Papule Diseases 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N Stearyl alcohol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- 229960000541 cetyl alcohol Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 239000003883 ointment base Substances 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- JKXYOQDLERSFPT-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO JKXYOQDLERSFPT-UHFFFAOYSA-N 0.000 description 2
- ICIDSZQHPUZUHC-UHFFFAOYSA-N 2-octadecoxyethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCO ICIDSZQHPUZUHC-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 229960001275 Dimeticone Drugs 0.000 description 2
- 208000007514 Herpes Zoster Diseases 0.000 description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 229940059904 Light Mineral Oil Drugs 0.000 description 2
- 206010067152 Oral herpes Diseases 0.000 description 2
- 201000003740 cowpox Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000003612 virological Effects 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- UGBLISDIHDMHJX-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-(2-methoxyphenyl)piperazin-1-yl]butan-1-one;hydrochloride Chemical compound [Cl-].COC1=CC=CC=C1N1CC[NH+](CCCC(=O)C=2C=CC(F)=CC=2)CC1 UGBLISDIHDMHJX-UHFFFAOYSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- SFAAOBGYWOUHLU-UHFFFAOYSA-N 2-ethylhexyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CC)CCCC SFAAOBGYWOUHLU-UHFFFAOYSA-N 0.000 description 1
- 230000035533 AUC Effects 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 240000007170 Cocos nucifera Species 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 208000000903 Herpes Simplex Encephalitis Diseases 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 229940078545 ISOCETYL STEARATE Drugs 0.000 description 1
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N Isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 206010023332 Keratitis Diseases 0.000 description 1
- 241000710944 O'nyong-nyong virus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940066842 Petrolatum Drugs 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940098760 STEARETH-2 Drugs 0.000 description 1
- 229940100458 STEARETH-21 Drugs 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- ULBTUVJTXULMLP-UHFFFAOYSA-N butyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCC ULBTUVJTXULMLP-UHFFFAOYSA-N 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000006082 chickenpox Diseases 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000008278 cosmetic cream Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940082337 dimethicone 20 Drugs 0.000 description 1
- 230000002497 edematous Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000010438 granite Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008251 pharmaceutical emulsion Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
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Abstract
There is provided an oil-in-water topical pharmaceutical formulation comprising a continuous aqueous phase comprising water, solubilised aciclovir and at least 30%by weight of a water miscible polyhydric alcohol, with a dispersed oil phase and dimethicone.
Description
COMPOSITIONS OF ACICLOVIR CONTAINING DIMETICONE
DESCRIPTION OF THE INVENTION This invention relates to a pharmaceutical, topical formulation suitable for use in the treatment of viral infections of the skin and mucosa, and in particular it relates to topical formulations containing 9- (2-hydroxyethoxymethyl) guanine, otherwise known as acyclovir, and later referred to as such. Acyclovir and pharmaceutically acceptable salts and esters thereof are known to have antiviral activity against various classes of viruses both in vi tro and in vi ve, see UK Patent No. 1 523 8th5. In particular, the compound is active against herpes viruses HSV1 and HSV2 (Herpes Simplex Virus type 1 and type 2) and VZV (varicella zoster virus) which are the cause of a range of infectious diseases in several species, especially chickenpox. or mad cowpox, herpes, genital herpes and cold sores (herpetic granites) in humans and diseases of the skin and mucosa in other animals, including keratitis in rabbits and herpetic encephalitis in mice. Acyclovir has been found to be effective in the treatment of herpes simplex virus infections and
REF: 131061 of zoster virus in humans. Further, references to acyclovir should be understood to also include its pharmaceutically acceptable salts and esters unless the context clearly dictates otherwise. Acyclovir suffers from the disadvantage that it has a low solubility in water and is almost totally insoluble in hydrophobic solvent systems. Accordingly, it is difficult to produce a topical formulation containing a sufficient dissolved concentration of the active ingredient so that it exerts its full effect and also to optimize the flow of the compound in the skin. Furthermore, to facilitate the 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 unduly irritate the skin. or the mucosa. European Patent No. 0 044 543 discloses topical, oil-in-water pharmaceutical formulations of acyclovir wherein the aqueous phase contains at least 30% of a water-miscible polyhydric alcohol. It has now been found that topical, oil-in-water pharmaceutical formulations of acyclovir comprising dimethicone and at least 25% by weight of a water-miscible polyhydric alcohol have particularly advantageous properties. In particular, such formulations exhibit surprisingly low irritation along with good physical stability and ease of application. A first aspect of the present invention therefore provides a pharmaceutical, topical, oil-in-water formulation of acyclovir comprising dimethicone and at least 25% by weight of a water-miscible polyhydric alcohol. A second aspect of the present invention provides a pharmaceutical, topical formulation comprising water, acyclovir, dimethicone, and at least 25% by weight of a water-miscible polyhydric alcohol of the formulation. A third aspect of the invention provides a pharmaceutical, topical formulation comprising acyclovir, dimethicone, and at least about 30% w / w of a water-miscible polyhydric alcohol formulation. Preferably, the topical pharmaceutical formulation is an oil-in-water formulation. A fourth aspect of the invention provides a pharmaceutical, topical oil-in-water formulation comprising a continuous aqueous phase and, dispersed therein, an aqueous phase, the formulation comprising water, solubilized acyclovir, dimethicone, and at least about 30% p / p of a water-miscible polyhydric alcohol. The preferred features of the first, second, third and fourth aspects of the invention are as follows. In a pharmaceutical formulation, topical according to the invention, the polyhydric alcohol can be present in the aqueous phase in an amount of above about 50% by weight. Preferably, the formation of the invention contains; at least 30% by weight of a polyhydric alcohol miscible in water and a maximum of 50% by weight of water of the formulation. Such a topical formulation may contain 0.075% a
% w / w acyclovir or a salt or ester thereof, of
% to 50% w / w of a polyhydric alcohol miscible in water, from 15% to 50% w / w of water, dimethicone and an oily phase. In a preferred aspect, the formulation comprises from 0.5% to 10% w / w of acyclovir, from 25% to 45% w / w of a polyhydric alcohol miscible in water and from 20% to 40% w / w of water together with an oily phase and dimethicone, while the most preferred formulation comprises from 1% to 5% w / w of acyclovir, from 30% to 40% w / w of a water-miscible polyhydric alcohol, from 25% to 40% w / w p of water, an oily phase and dimethicone. The dimethicone may be present in an amount sufficient to significantly decrease the irritation of the composition, for example in an amount of 0.1% to 10% by weight of the formulation, preferably from 0.1% to 5.0% by weight. In the most preferred formulations, dimethicone will be present in an amount of 0.5% to 1.5% by weight of the formulation. Dimethicones, also known as polydimethylsiloxane, is a silicone oil consisting of a mixture of linear, fully methylated siloxane polymers ending in block with trimethylsiloxy units. It finds use as an emollient or slip agent in cream-based pharmaceutical formulations. A polyhydric alcohol is an alcohol having two or more hydroxyl groups. Water-miscible polyhydric alcohols suitable for incorporation into the formulations of the present invention include glycols and macrogols such as propylene glycol, butane 1,3-diol, polyethylene glycol, glycerol and diethylene glycol monoethyl ether, the preferred alcohol being propylene glycol. The formulations of the invention may comprise from 25% to 50% of propylene glycol, for example from 25% to 45% by weight, desirably from 35% to 45% by weight, particularly 40% by weight of the formulation. The formulation of the invention may be a pharmaceutical, topical formulation of oil in water wherein the polyhydric alcohol is propylene glycol, for example where the propylene glycol is present in an amount of 30% to 45% w / w of 30% to 40% p / p. The oily phase of the emulsions of this invention can be constituted of known ingredients in a known manner. While the oily phase may comprise only one emulsifier (otherwise known as an emulsifier), 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. Preferably, as explained in more detail below, a hydrophilic emulsifier is included in conjunction with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without the stabilizer (s) complete the wax commonly called emulsifier, and the wax together with the oil and / or fat complete the base of ointment commonly called emulsifier which it forms the oily, dispersed phase of the emulsions. Emulsifiers and emulsion stabilizers, suitable for use in the formulation of the present invention, include cetyl alcohol, sodium lauryl sulfate, stearyl alcohol and polyoxyethylene alkyl ethers, such as polyoxystearyl ethers, for example steareth 2 and steareth 21. The selection of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of acyclovir in most of the oils likely to be used in pharmaceutical emulsion formulations is very low. In this way, the cream should preferably be a non-greasy, non-coloring and washable product with a suitable consistency to prevent the escape of tubes or other containers. Straight or branched mono- or dialkyl esters such as diisopropyl adipate, isocetyl stearate, propylene glycol diester of coconut fatty acids can be used, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a mixture of cetyl or stearyl alcohols known as Crodamol CAP, the last three being the favorite esters. These can be used individually or in combination depending on the required properties. Alternatively, high melting point lipids such as mild paraffin and / or liquid, white paraffin or other mineral oils can be used. A preferred formulation according to the invention comprises 0.5-1.5% w / w of dimethicone; about 5% w / w acyclovir; 5-10% w / w cetostearyl alcohol; 35-45% w / w of propylene glycol; 2-10% w / w of mineral oil; 10-15% w / w of white petrolatum, 0.5-1% w / w of sodium lauryl sulphate; 0.5-2% w / w poloxamer 407 and purified water at 100% w / w. The formulations of the invention may, if desired, include one or more pharmaceutically acceptable preservatives. However, it has been found that the use of preservatives is not essential in the formulations of the invention, a discovery that represents an advantage of the formulations.
The formulations of the invention may, if desired, include one or more pharmaceutically acceptable excipients such as colors, fragrances, and other excipients known to those skilled in the art of preparing topical formulations and cosmetic creams. All such excipients must be pharmaceutically acceptable "in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.A method for the treatment of a viral infection caused by a member of the family is also provided. virus herpes comprising the topical administration of a pharmaceutically effective amount of a formulation according to the present invention The present invention also provides the use of dimethicone in the reduction of the irritation of the oil-in-water, acyclovir topical formulations which comprise at least 25% w / w, preferably at least 30% w / w, of a water-miscible polyhydric alcohol The present invention also provides the use of acyclovir, dimethicone and at least 30% w / w of a water-miscible polyhydric alcohol in the preparation of a topical medication for the treatment of viral infections of the herpes family.
The present invention further provides a method for the preparation of a topical pharmaceutical formulation, as defined above, which comprises mixing the combination of acyclovir, polyhydric alcohol miscible in water and water with an oily phase and dimethicone to form a creamy emulsion . The manner of formulation of the emulsion will, of course, vary according to the amount and nature of the constituents, but nevertheless the techniques known in emulsion technology are followed (see the Pharmaceutical Codex, London, the Pharmaceutical Press, 1979). For example, acyclovir and water-miscible polyhydric alcohol can be fully incorporated in the aqueous portion where they can form a solution, or a mixed solution / suspension, and then emulsified with an ointment base and dimethicone. Alternatively, where high concentrations of acyclovir are being used, a portion of the aqueous portion can be formulated with an ointment base as an emulsion, and the rest of the water-miscible polyhydric alcohol and acyclovir is added and dispersed in the emulsion In another technique, acyclovir can be included in the emulsifying ointment prior to emulsification with the aqueous portion. In the use of these methods, it is preferred to heat the aqueous portion and the ointment base to about 40 to 80 ° C, preferably 50 to 70 ° C, prior to emulsification, which can be achieved by vigorous stirring using example a laboratory mixer, normal. The finer dispersions of the oily phase can be obtained by homogenization or grinding in a colloid mill. A topical formulation of the present invention can be used in the treatment or prevention of viral infections caused for example by Herpes zoster, Herpes varicella and Herpes simplex types 1 and 2, which cause diseases such as herpes, varicella or mad cowpox, herpes labial and genital herpes. The formulation should be applied in a desirable manner to the affected area of the skin 1 to or more times a day, preferably 3 to 5 times. The following examples illustrate the invention and are not proposed as a limitation thereof.
Example 1 Ingredient% w / w TRANSCUTOLMR 40.0 Acyclovir 5 0 stearyl alcohol 5.0 cetyl alcohol 4.0 light mineral oil 10.2 brij 721 2.5 brij 72 2 3 dimethicone 20 1.5 purified water at 100
The oily phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75 ° C with mixing and the dimethicone is added. The purified water is heated to O5-70CC and added to the oily phase, maintaining the temperature at 70-75 ° C, with mixing to form an emulsion. The mixture is maintained at a temperature of 70-75 ° C for about 5 minutes. The TRANSCVTOLMR is weighed into an appropriate container and acyclovir is added with mixing to form a suspension. The acyclovir suspension is added to the emulsion, rinsed with a small amount of purified water. The emulsion is homogenized for about 5 minutes, then it is completed for the weight of the final batch with purified water. The resulting cream is cooled to room temperature (about 30 ° C) with continuous mixing before the cream is filled into suitable tubes which are then sealed.
Example 2 Ingredient% w / w Acyclovir 5.0 Mineral oil 5.0 White petrolatum 11.5 Sodium lauryl sulfate 0.75 Cetostearyl alcohol 0.75 Propylene glycol 40.0 Poloxamer 407 1.0 Dimethicone 1.0 Purified water at 100 In vessel 1, poloxamer 407 was dissolved in purified water , cold. Then the propylene glycol was added and mixed to form the aqueous phase. A small portion of the aqueous phase was removed and added to the acyclovir powder in a second kettle, and an acyclovir dispersion was formed. The aqueous phase remaining in vessel 1 was heated to 70 ° C - 80 ° C. The emulsifying wax was prepared in vessel 3 by heating together with the cetostearyl alcohol, sodium lauryl sulfate and a small amount of purified water at 115 ° C until the foaming stopped. The prepared emulsifying wax was melted together with the soft, white petrolatum, the dimethicone and the mineral oil and the mixture was heated to 73-77 ° C. The hot aqueous phase was then added to vessel 3 and the mixture was emulsified. The emulsion was cooled to 45-55 ° C. The acyclovir suspension was added and mixed well. The cream was cooled down to 40 ° C and transferred to a holding vessel, before being filled into suitable tubes which were then sealed.
Example 3 The formulation described in Example 1 can be prepared alternatively by the following modified procedure. The oily phase is weighed and heated to 73-77 ° C and the dimethicone is added, with slow, continuous mixing. The purified water is heated to 65-70 ° C. Purified water is added with propeller agitation to the acyclovir suspension in TRANSCUTOL ™. The resulting aqueous mixture is heated to 65-70 ° C. While maintaining the temperature of the oily phase at 70-75 ° C, the aqueous phase is added slowly with stirring or swirling for at least 5 minutes. The container of the aqueous phase is rinsed with purified water and the rinses are added to the main batch. The batch temperature 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 stirring or swirling, continuous and purified water is added to adjust the weight of the final batch. The batch is mixed until uniform and cooled to 30 ° C before the cream is filled into suitable tubes which are then sealed.
Example 4 5% acyclovir cream (marketed under ® trademark ZOVIPUX by Glaxo Wellcome, Glaxo
Wellcome House, Berkeley Avenue Greenford, Middlesex,
UB6 ONN) consists of acyclovir solubilized in the aqueous phase of the oil-in-water cream base known as WMAC-P ".
MAC-P Cream Base:% w / w Propylene Glycol 40.00 Cetostearyl Alcohol 6.75 Sodium Lauryl Sulfate 0.75 Poloxamer 407 (Pluronic F127MR) 1.00 Soft White Paraffin (Petrolatum) 12.50 Liquid Paraffin (Ace = Mineral Ore) 5.00 Purified Water at 100.00 formulation is very similar to that of Example 2 and is done in the same way; for the MAC-P cream base, acyclovir is omitted, for the cream
® ZOVIRAX, 5% w / w acyclovir is included. The cream
MACP, with or without acyclovir, can also be formulated with dimethicone, which is added to the oily phase which is maintained at. 13- 11 ° C
Experimental Data The guinea pig infection model with herpes simplex virus (HSV) was used to compare the ® formulation of ZOVIRAX (5% w / w acyclovir cream)
MAC-P) with MAC-P plus 1% dimethicone and with MAC-P plus 1% dimethicone and 5% acyclovir (made as indicated above in examples 2 and 4).
Cobayo Model: The model of guinea pig infection with HSV is characterized by a self-limiting skin disease which provides a useful model in the evaluation and development of topical HSV therapies. The disease produced by experimentally infecting guinea pigs with HSV mimics infection in humans in the clinical onset, progression of the disease and duration of the lesions.
Infection process: The guinea pigs, hairless, female (Ibm: GOHI-hr) weighing between 550 g and 600 g (BRL Bilogical Research Laboratories Limited, Wolferstrasse 4, CH-4414 Fullinsdorf, Switzerland), sedated with an intramuscular injection of Hypnorm 0.6 ml / kg (Janssen Animal Health, High Wycombe, UK), were inoculated on the left side in six discrete sites. This infection procedure involved light scarification of the surface of the skin through a drop of 20 ID of viral suspension (virus titer, final 3x105 pfu / 20 ID) at each site, using a spike device multiple, disposable with 6 x 2 mm tips (Bignell Surgical Supplies, Littlehampton, West Sussex, UK).
Treatment Regime: A total of 25 animals were used in this study. Seven animals were assigned to the untreated control group and six to each of the three treatment groups: 1. No treatment (virus control) 2. 1% dimethicone in MAC-P ® 3. 5% acyclovir in MAC -P (ZOVIRAX) 4. 1% dimethicone + 5% acyclovir in MAC-P
The therapy consisted of 1 ml (approximately 1 g) of test cream, supplied from a 5 ml syringe, possibly extended on the infected side twice a day (8:00 a.m. and 5.00 p.m.). Treatment of the infected animals began 18 hours after infection and continued for three days, with each animal receiving a total of six applications.
Progress of the Disease: During the normal course of infection, the inoculation sites become erythematous and edematous by day 1 after infection (p.i.), the degree of which increases over the subsequent days. The appearance of papules, which develop subsequently in postoles, is generally observed for 2 to 3 days p.i. the size and number of the pustules increases as the infection progresses and, if they are juxtaposed, they will eventually join. The peak of infection is generally observed by day 6-7 p.i. when the joined lesions begin to crush.
Determination of the Antiviral Effect In order to determine the progress of the disease, a daily assessment of each animal is made. This involved the registration of each of the infection sites according to the criteria set out below:
0. 0 = no signs of visible infection 0.5 = very recent papules (not increased) light erythema 1.0 = papules and erythema 2.0 = 0-5 pustules and erythema 3.0 = 6+ pustules and erythema 4.0 = coalescence of pustules 5.0 = coated / encrusted the pustules
The first assessment is carried out immediately before the start of treatment and was repeated on days 2, 3, 4 and 3 after infection. As the titration method is based on the natural progression of the disease in guinea pigs, a reduction for treated animals over untreated animals indicates an antiviral effect. The daily records for each side were totaled and the average record per side per day was calculated. The areas under the curve (AUCs) for all treatment groups and the control group were calculated and subjected to statistical analysis to determine the meaning.
Determination of Erythema A visual inspection of each animal was made at the time of treatment and the degree of erythema on each side was observed. This erythema related to treatment was assigned to one of five categories: 1 without erythema 2 light erythema 3 moderate erythema 4 substantial erythema 5 severe erythema
Results: The results for antiviral activity are shown in tables la-d, table 2 and figure 1 and for erythema in table 3.
Antiviral All animals in the control group reached the maximum possible injury record by day 8 p.i. Animals treated with placebo (group 2:
1% Dimethicone in MAC-P) developed a disease profile that closely resembles the control group, which shows that 1% dimethicone cream offers no antiviral benefit. The treatment with both
® ZOVIRAX and 1% Dimethicone + 5% acyclovir in MAC-P creams results in a reduction in the development of the lesion after only two applications of the therapy. In both cases, this reduction continued with the additional applications of the treatment, which results in few signs of clinical infection that remain visible by the 8th day after infection.
Table the individual injury records - Viral control group
Table Ib Individual lesion records - 1% Dimeticone / Zovirax placebo group
Table of records of individual injuries - Treaty group with Zovirax
Table Id Records of individual lesions - Group treated with 1% dimethicone / Zovirax (DZ)
Table 2 Average records per side
The statistical analysis of the data generated suggested a highly significant difference between the control and the groups treated with placebo and the groups ® treated with Zovirax and 1% Dimethicone + 5% acyclovir (p <0.001). However, there was no evidence of ® a significant difference between Zorivax and 1% of
Dimethicone + 5% acyclovir in the MAC-P groups
(p = 0.34).
Erythema As can be seen from Table 3, substantial erythema was observed after treatment ® with Zopvax, while light erythema was only observed after treatment with 1%
Dimethicone + 5% acyclovir in MAC-P cream (DZ).
Erythema associated with the treatment
where 0 = no erythema x = light erythema xx = moderate erythema xxx = substantial erythema xxxx = severe erythema
Discussion: The secondary effect of erythema related to the treatment has been observed frequently in animals treated with Zovirax, which can lead to cracking and peeling of the skin. From the observations made in this study it is apparent that the addition of 1% Dimethicone to the formulation results in a significant reduction in the level of erythema associated with the treatment, while maintaining the high level of antiviral activity.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (17)
- Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical formulation, topical, characterized in that it comprises water, acyclovir, dimethicone and at least about 25% of a water-miscible polyhydric alcohol of the formulation .
- 2. A pharmaceutical formulation, oil-in-water topical, of acyclovir characterized in that it comprises dimethicone and at least 25% of a polyhydric alcohol miscible with water by weight of the formulation.
- 3. A topical pharmaceutical formulation characterized in that it comprises acyclovir, dimethicone and at least about 30% w / w of a water-miscible polyhydric alcohol.
- 4. A pharmaceutical formulation, topical according to claim 1, characterized in that it is an oil-in-water formulation.
- 5. A pharmaceutical formulation, topical, oil-in-water, characterized in that it comprises a continuous aqueous phase, and dispersed therein, an oily phase, the formulation comprises water, solubilized acyclovir, dimethicone and at least about 30% w / w of an alcohol polyhydric miscible in water.
- 6. A pharmaceutical, topical formulation according to any of claims 1 to 5, characterized in that it contains at least 30% by weight of a polyhydric alcohol miscible in water and a maximum of 50% water by weight of the formulation.
- 7. A pharmaceutical, topical formulation according to any of claims 1 to 6, characterized in that the polyhydric alcohol is present in the aqueous phase in an amount above about 5C% by weight.
- 8. A pharmaceutical, topical formulation according to any of claims 1 to 7, characterized in that it contains 0.075% to 10% w / w acyclovir or salts or esters thereof, from 25% to 50% w / w of a polyhydric alcohol miscible in water, from 15% to 50% w / w of water, dimethicone and an oily phase.
- 9. A pharmaceutical, topical, oil-in-water formulation according to any of claims 1 to 8, characterized in that the polyhydric alcohol is propylene glycol.
- 10. A topical pharmaceutical formulation according to claim 9 characterized in that the propylene glycol is present in an amount of 25% to 50% by weight of the formulation.
- 11. An oil-in-water topical pharmaceutical formulation according to claim 1 to 2 or 4 to 8 characterized in that the polyhydric alcohol is propylene glycol in which it is present in an amount of 30% to 45% by weight.
- 12. A topical pharmaceutical formulation according to any of the preceding claims characterized in that the dimethicone is present in an amount sufficient to significantly decrease the irritation of the formulation.
- 13. A pharmaceutical formulation, topical, according to any of the preceding claims, characterized in that the dimethicone is present in an amount between 0.1% to 10% by weight of the formulation.
- 14. A pharmaceutical formulation, topical, according to any of the preceding claims, characterized in that the dimethicone is present in an amount between 0.5% and 1.5% by weight of the formulation.
- 15. The use of acyclovir, dimethicone and at least 30% w / w of a water-miscible polyhydric alcohol in the preparation of a topical medicament for the treatment of viral infections of the herpes family.
- 16. The use of dimethicone in the reduction of the irritation of oil-in-water formulations, characterized in that it comprises at least 25% w / w of a water-miscible polyhydric alcohol.
- 17. A method for treating a viral infection caused by a member of the herpes virus family characterized in that it comprises the topical administration of a pharmaceutically effective amount of a formulation according to any one of claims 1 to 14. PESUMEN OF THE INVENTION A pharmaceutical, topical, oil-in-water formulation comprising a continuous aqueous phase comprising water, solubilized acyclovir, and at least 30% by weight of a water miscible polyhydric alcohol, with an oily, dispersed phase and dimethicone is provided.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9828620.6 | 1998-12-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01006490A true MXPA01006490A (en) | 2002-05-09 |
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