WO2000001390A1 - Topical aciclovir formulations - Google Patents

Topical aciclovir formulations Download PDF

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Publication number
WO2000001390A1
WO2000001390A1 PCT/EP1999/004606 EP9904606W WO0001390A1 WO 2000001390 A1 WO2000001390 A1 WO 2000001390A1 EP 9904606 W EP9904606 W EP 9904606W WO 0001390 A1 WO0001390 A1 WO 0001390A1
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Prior art keywords
pharmaceutical composition
aciclovir
accordance
fact
esters
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PCT/EP1999/004606
Other languages
French (fr)
Inventor
Giancarlo Santus
Luciano Marcelloni
Roberto Golzi
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Recordati S.A. Chemical And Pharmaceutical Company
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Priority to AU49054/99A priority Critical patent/AU4905499A/en
Publication of WO2000001390A1 publication Critical patent/WO2000001390A1/en

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    • 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
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • Object of the present invention are topical formulations useful in the treatment of viral infections of the skin and mucous membranes, which contain the active ingredient 9-(2-hydroxymethoxymethyl)guanine, known as aciclovir, and are characterised by the inclusion of sucrose esters as absorption promoters.
  • the present invention relates to topical formulations for the administration of aciclovir, which contain a sucroester as an element promoting absorption of the active ingredient through the skin.
  • the sucroesters are sucrose esters obtained by reaction of sucrose with one or more fatty acids having a linear chain with an even number of carbon atoms ranging from 12 to 18, are widely used and have many applications in the pharmaceutical and food fields. These esters are commercially known by the name SUCROESTER ® (Gattefosse S.A. - Saint Priest - France) or CRODESTA ® (Croda Surfactants Ltd. - Goole - UK).
  • Sucroesters belong to the class of non-ionic surfactants, are endowed with good stability and do not undergo - after preparation of the finished products - any hydrolytic processes of a chemical or enzymatic nature. Being made up of a sugar with fatty acids, they are absolutely harmless compounds and not at all aggressive against the skin, thus being an excipient capable of meeting all of the cosmetic requirements of a topical preparation. Description of invention
  • sucrose ester when added to the ingredients of topical formulations for the administration of aciclovir via emulsified mixtures of lipids in water, these formulations become particularly effective in improving absorption and tolerance of aciclovir compared to both the commercial formulations and those described in the previous art.
  • the topical formulations which are an object of the invention comprise: from 0.1% to 10% w/w of aciclovir or any of its salts or any of its esters; from 0.1 % to 40% w/w of a sucrose ester; from 20% to 40% w/w of water, incorporated in a mixture with an oily phase.
  • the lipidic component of the emulsion is made up of known materials and is emulsified with the aqueous component in accordance with processes known in the art.
  • One or more emulsifying agents can be added to the ingredient of the lipidic phase, which can be a fat or an oil, to make the emulsion stable in time.
  • the ingredients of the oily phase are chosen predominantly on the basis of the cosmetic characteristics desired in the finished products since the solubility of aciclovir in oils and fats is confined to a limited range.
  • Example of the lipidic materials which can be used are linear or branched mono- or dialkylesters of esters of fatty acids such as, for example, isopropylmyristate and isopropylpalmitate, mixtures of cetyl and stearyl alcohol known by the commercial name Crodamol ® , high-molecular-weight lipids such as white paraffin or liquid paraffin and other mineral oils.
  • emulsifiers and emulsion stabilising agents include cetyl alcohol, sodium lauryl sulphate, stearyl alcohol, polyoxyethylene alkylesters such as Brij ® 72 and 721 and polyoxystearyl esters such as Steareth ® 2 and 21.
  • the aqueous phase of the emulsion can also contain other ingredients such as glycerine and glycol.
  • the amount of these ingredients is preferably lower than 30%.
  • an amount higher than 30% of polyalcohols such as glycerine and glycol is normally added to the aqueous phase to be used for the emulsion in order to increase aciclovir solubility in the phase.
  • esters of sucrose to the formulation ingredients allows these amounts of glycol in the formulation to be reduced far below 30%, at the same time increasing the therapeutic and cosmetic efficacy of the formulation thanks to the ability of sucroesters to act as promoters of the absorption of the active ingredient through the skin.
  • the sucroesters being substances which result from the combination of sucrose with normal food fats and, in particular, myristic acid, oleic acid, palmitic acid or stearic acid, they have a molecular structure with amphiphilic characteristics, both lipophilic and hydrophilic. These amphiphilic characteristics can be appropriately modulated using the sucroester most suitable for the various absorption requirements. In fact, the higher the number of sugar hydroxyls substituted by fatty acids, the more the lipophilic characteristics of sucroesters increase, and vice versa.
  • the sucroesters are thus capable of acting as absorption promoters, helping permeation of substances which would otherwise be poorly absorbed.
  • the monoesters are particularly useful in helping formation of oil-in-water emulsions.
  • the sucrose monoesters are scarcely soluble in cold water, while they are soluble in hot water, ethyl alcohol and acetone.
  • Their amphiphilic characteristics are represented by HLB (Hydrophilic Lypophilic Balance) values which can range from 7 to 14. For example: sucrose monopalmitate (HLB 14), sucrose mono/distearate (HLB 11 ), sucrose distearate (HLB 7).
  • sucrose monopalmitate is preferred among the monoesters for its high HLB value which, in addition to helping formation of an oil-in-water emulsion, contributes to stabilising it.
  • composition ratios (w/w) for a formulation suitable for the administration of aciclovir according to the present invention include: sucrose monopalmitate 15%, aciclovir 5%, cetostearyl alcohol 3-10%, propylene glycol 5- 30%, mineral oil 5-15%, Steareth ® 21 2-5%, sodium lauryl sulphate 0.1-1%, purified water as needed to reach 100%.
  • preservatives such as, for example, p- oxybenzoates, sodium benzoate, benzalkonium chloride and the like, can be added to these formulations as a precautionary complement in case of long-term storage.
  • a process to prepare the above topical formulations, too, is an integrant part of the invention. This process consists in stirring aciclovir or any of its salts or esters, a sucrose ester, the active ingredients, the excipients making up the oily phase and those making up the aqueous phase in a suitable emulsifier, up to formation of an oil/water emulsion.
  • the method of formulating the emulsion can vary depending on the amount and nature of the ingredients and follows the processes known in emulsion formation described, for example, in A. R. Gennaro: “Remington: The Science and Practice of Pharmacy", 19th Ed., Ch. 21 , 282-291 , Mack Publ. Co. (1995).
  • the preferred method is that of hot(70°C)-suspending aciclovir in the aqueous phase together with the sucrose esters, sodium lauryl sulphate, propylene glycol and to finally add this mixture to the ingredients of the fatty phase kept in a melted state at a temperature of about 60 to 70°C.
  • the emulsion forms after the addition of the aqueous phase to the vigorously-stirred oily phase.
  • the preferred apparatus for formation of the emulsion is a turboemulsifier, which allows vigorous stirring under vacuum, thus avoiding incorporation of air and the consequent formation of bubbles in the final cream.
  • the topical formulation prepared in accordance with the invention can be used for the treatment or prevention of viral infections caused by Herpes zoster, Herpes varicella and type-1 or 2 Herpes simplex. In particular, it was found to be useful in cases of Herpes labialis.
  • the formulation should be applied to the skin 1 to 6 times daily, preferably from 3 to 5 times.
  • formulations referred to in the present invention can easily adapt to the topical administration of other antiviral analogues of aciclovir such as, for example, famciclovir, penciclovir, valaciclovir and the like, or their synergetic combinations with other antiviral agents such as derivatives of guanine, vidarabine, citarabine and the like.
  • An oily phase was prepared by melting a mixture made up of stringy petrolatum, mineral oil and cetostearyl alcohol at 60°C.
  • An aqueous solution made up of sodium lauryl sulphate, Poloxamer ® 407, propylene glycol, sucrose monopalmitate and water in which micronised aciclovir had been hot(60°C)-dispersed was slowly added to the hot-stirred oily phase, and allowed to cool to ambient temperature.
  • the cream which formed was filled into 10-gram aluminium tubes internally coated with epoxy resin.
  • An oily phase was prepared by melting at 60°C made up of stringy petrolatum, mineral oil and cetostearyl alcohol.
  • An aqueous phase made up of sodium lauryl sulphate, Poloxamer ® 407, propylene glycol, sucrose distearate and water in which micronised aciclovir had been hot(70°C)-suspended, was added to the oily phase. Addition was slow with continuous hot-stirring, and cooling to ambient temperature was allowed. The cream which formed was filled into 5-gram aluminium tubes internally coated with epoxy resin.
  • An oily phase made up of stringy petrolatum, mineral oil, cetyl and stearyl alcohol was prepared by melting at 60°C.
  • a fatty phase made up of stringy petrolatum, mineral oil and cetostearyl alcohol
  • the temperature was brought to 60°C and the ingredients were allowed to melt for about 30 minutes.
  • Water, sodium lauryl sulphate, Poloxamer® 407 were separately added into a 5-L dissolution tank and the mixture was heated to 70°C. After complete dissolution of the mixture, propylene glycol and sucrose monopalmitate were added and stirred for about 30 minutes at a temperature of 70°C. After achieving again complete dissolution, micronised aciclovir was added and suspended with stirring using an UltraTurrax ® homogeniser, and a constant temperature was maintained.
  • Example 1 The cream described in Example 1 was compared with the above commercial cream Zovirax ® using a percutaneous absorption apparatus (Crown Glass Company, New Jersey, USA) which uses continuous-flow Bronaugh cells to measure permeation through the skin of Guinea pigs (R. Bronaugh et al., Journal Pharmaceutical Sciences, 74, 64-67 (1985)).
  • the skin of Guinea pigs was mounted on Bronaugh cells having a surface of 0.3 sq.cm. to which an amount of cream equal to 200-250 mg was applied.
  • a solution of phosphate buffer pH 7.4 was circulated for 48 hours and the various fractions were collected every 8 hours.
  • the collected fractions were analysed by a reverse- phase HPLC method using a Waters-625 apparatus with a C18 ⁇ Bondapack column, injecting 20 ⁇ l, eluting with the mobile phase water:methanol:acetic-acid (840/160/1 ) at a rate of 1 ml/minute, determining absorption with a UV detector at 254 nm.
  • Table 1 The results of the permeation test are shown in Table 1 below: TABLE 1
  • Example 1 could permeate through the skin layer in 48 hours an amount of aciclovir higher by at least 25% than the amount which was permeated by the commercial reference formulation Zovirax ® 5% Cream. Based on this, the formulation which is an object of the invention allows improved drug permeation through the skin and induces improved drug absorption and, as a result, improved therapeutic efficacy.

Abstract

Described are topical formulations for the administration of aciclovir. These formulations can be used in the preventive and therapeutic treatment of infections from Herpes virus and are characterised by the presence of sucrose esters as promoters of active ingredient absorption.

Description

TOPICAL ACICLOVIR FORMULATIONS Field of invention
Object of the present invention are topical formulations useful in the treatment of viral infections of the skin and mucous membranes, which contain the active ingredient 9-(2-hydroxymethoxymethyl)guanine, known as aciclovir, and are characterised by the inclusion of sucrose esters as absorption promoters. Previous art
Aciclovir, its salts and the esters derived from it, have long been known for their antiviral action, as extensively described in the British patent GB 1 ,523,865. Several topical formulations containing aciclovir have been described in the previous art. In particular, patent EP 44,543 describes formulations of aciclovir in oil/water mixtures which contain at least 30% of a polyvalent alcohol miscible with water, and patent application WO 97/34,607 describes topical oil-in-water formulations containing at least 10% diethylene glycol monoethylether known by the commercial name Transcutol®.
The present invention relates to topical formulations for the administration of aciclovir, which contain a sucroester as an element promoting absorption of the active ingredient through the skin. The sucroesters are sucrose esters obtained by reaction of sucrose with one or more fatty acids having a linear chain with an even number of carbon atoms ranging from 12 to 18, are widely used and have many applications in the pharmaceutical and food fields. These esters are commercially known by the name SUCROESTER® (Gattefosse S.A. - Saint Priest - France) or CRODESTA® (Croda Surfactants Ltd. - Goole - UK). Sucroesters belong to the class of non-ionic surfactants, are endowed with good stability and do not undergo - after preparation of the finished products - any hydrolytic processes of a chemical or enzymatic nature. Being made up of a sugar with fatty acids, they are absolutely harmless compounds and not at all aggressive against the skin, thus being an excipient capable of meeting all of the cosmetic requirements of a topical preparation. Description of invention
It has now been found, and it is an object of the present invention, that, when a sucrose ester is added to the ingredients of topical formulations for the administration of aciclovir via emulsified mixtures of lipids in water, these formulations become particularly effective in improving absorption and tolerance of aciclovir compared to both the commercial formulations and those described in the previous art.
The topical formulations which are an object of the invention comprise: from 0.1% to 10% w/w of aciclovir or any of its salts or any of its esters; from 0.1 % to 40% w/w of a sucrose ester; from 20% to 40% w/w of water, incorporated in a mixture with an oily phase.
The lipidic component of the emulsion is made up of known materials and is emulsified with the aqueous component in accordance with processes known in the art. One or more emulsifying agents can be added to the ingredient of the lipidic phase, which can be a fat or an oil, to make the emulsion stable in time. The ingredients of the oily phase are chosen predominantly on the basis of the cosmetic characteristics desired in the finished products since the solubility of aciclovir in oils and fats is confined to a limited range. Example of the lipidic materials which can be used are linear or branched mono- or dialkylesters of esters of fatty acids such as, for example, isopropylmyristate and isopropylpalmitate, mixtures of cetyl and stearyl alcohol known by the commercial name Crodamol®, high-molecular-weight lipids such as white paraffin or liquid paraffin and other mineral oils. Examples of emulsifiers and emulsion stabilising agents include cetyl alcohol, sodium lauryl sulphate, stearyl alcohol, polyoxyethylene alkylesters such as Brij® 72 and 721 and polyoxystearyl esters such as Steareth® 2 and 21. In addition to water, the aqueous phase of the emulsion can also contain other ingredients such as glycerine and glycol. However, the amount of these ingredients is preferably lower than 30%. Based on what described in the previous art (EP 044 543), an amount higher than 30% of polyalcohols such as glycerine and glycol is normally added to the aqueous phase to be used for the emulsion in order to increase aciclovir solubility in the phase.
However, the presence of an amount of propylene glycol in amounts higher than 30% can cause poor-skin-tolerance reactions due to the dehydrating action peculiar to this glycol. This is particularly important when the topical preparation is to be applied onto areas of skin which is no longer sound, as is the case of lesions caused by Herpes labialis.
It has now been found, and it is an object of the invention, that the addition of esters of sucrose to the formulation ingredients allows these amounts of glycol in the formulation to be reduced far below 30%, at the same time increasing the therapeutic and cosmetic efficacy of the formulation thanks to the ability of sucroesters to act as promoters of the absorption of the active ingredient through the skin. The sucroesters being substances which result from the combination of sucrose with normal food fats and, in particular, myristic acid, oleic acid, palmitic acid or stearic acid, they have a molecular structure with amphiphilic characteristics, both lipophilic and hydrophilic. These amphiphilic characteristics can be appropriately modulated using the sucroester most suitable for the various absorption requirements. In fact, the higher the number of sugar hydroxyls substituted by fatty acids, the more the lipophilic characteristics of sucroesters increase, and vice versa.
Thanks to the contemporary presence of hydrophilic and lipophilic groups in the molecule and the resulting ability of distribution in the skin layers with lipophilic characteristics (the horny layer) and the layers with hydrophilic characteristics (the dermis), the sucroesters are thus capable of acting as absorption promoters, helping permeation of substances which would otherwise be poorly absorbed. Among the various types of sucroesters, the monoesters are particularly useful in helping formation of oil-in-water emulsions. The sucrose monoesters are scarcely soluble in cold water, while they are soluble in hot water, ethyl alcohol and acetone. Their amphiphilic characteristics are represented by HLB (Hydrophilic Lypophilic Balance) values which can range from 7 to 14. For example: sucrose monopalmitate (HLB 14), sucrose mono/distearate (HLB 11 ), sucrose distearate (HLB 7).
For a typical implementation of the present invention, sucrose monopalmitate is preferred among the monoesters for its high HLB value which, in addition to helping formation of an oil-in-water emulsion, contributes to stabilising it.
The preferred composition ratios (w/w) for a formulation suitable for the administration of aciclovir according to the present invention include: sucrose monopalmitate 15%, aciclovir 5%, cetostearyl alcohol 3-10%, propylene glycol 5- 30%, mineral oil 5-15%, Steareth® 21 2-5%, sodium lauryl sulphate 0.1-1%, purified water as needed to reach 100%.
Optionally, although it has been found that the addition of these preservatives is not strictly necessary for storage in time of the topical formulations described in the present invention, one or more preservatives such as, for example, p- oxybenzoates, sodium benzoate, benzalkonium chloride and the like, can be added to these formulations as a precautionary complement in case of long-term storage.
A process to prepare the above topical formulations, too, is an integrant part of the invention. This process consists in stirring aciclovir or any of its salts or esters, a sucrose ester, the active ingredients, the excipients making up the oily phase and those making up the aqueous phase in a suitable emulsifier, up to formation of an oil/water emulsion.
The method of formulating the emulsion can vary depending on the amount and nature of the ingredients and follows the processes known in emulsion formation described, for example, in A. R. Gennaro: "Remington: The Science and Practice of Pharmacy", 19th Ed., Ch. 21 , 282-291 , Mack Publ. Co. (1995).
The preferred method is that of hot(70°C)-suspending aciclovir in the aqueous phase together with the sucrose esters, sodium lauryl sulphate, propylene glycol and to finally add this mixture to the ingredients of the fatty phase kept in a melted state at a temperature of about 60 to 70°C. The emulsion forms after the addition of the aqueous phase to the vigorously-stirred oily phase.
The preferred apparatus for formation of the emulsion is a turboemulsifier, which allows vigorous stirring under vacuum, thus avoiding incorporation of air and the consequent formation of bubbles in the final cream.
The topical formulation prepared in accordance with the invention can be used for the treatment or prevention of viral infections caused by Herpes zoster, Herpes varicella and type-1 or 2 Herpes simplex. In particular, it was found to be useful in cases of Herpes labialis. The formulation should be applied to the skin 1 to 6 times daily, preferably from 3 to 5 times.
It is also obvious that the formulations referred to in the present invention, even though they are conceived in particular for the administration of aciclovir and its derivatives, can easily adapt to the topical administration of other antiviral analogues of aciclovir such as, for example, famciclovir, penciclovir, valaciclovir and the like, or their synergetic combinations with other antiviral agents such as derivatives of guanine, vidarabine, citarabine and the like.
Provided below are some examples which are only meant to better describe the subject invention and show its advantages and applicability, but without being a limitation of same.
EXAMPLE 1
Aciclovir 5 %
Sucrose 15% monopalmitate
Cetostearyl alcohol 6.75%
Propylene glycol 20%
Sodium lauryl sulphate 0.75%
Poloxamer 407 1%
Mineral oil 5%
Stringy petrolatum 12.5%
Water 34%
An oily phase was prepared by melting a mixture made up of stringy petrolatum, mineral oil and cetostearyl alcohol at 60°C. An aqueous solution made up of sodium lauryl sulphate, Poloxamer® 407, propylene glycol, sucrose monopalmitate and water in which micronised aciclovir had been hot(60°C)-dispersed was slowly added to the hot-stirred oily phase, and allowed to cool to ambient temperature. The cream which formed was filled into 10-gram aluminium tubes internally coated with epoxy resin.
EXAMPLE 2
Micronised aciclovir 5 %
Sucrose distearate 20%
Cetostearyl alcohol 6.75%
Propylene glycol 20%
Sodium lauryl sulphate 0.75%
Poloxamer® 407 1 %
Mineral oil 5%
Stringy petrolatum 12.5%
Water q.s. to 100%
An oily phase was prepared by melting at 60°C made up of stringy petrolatum, mineral oil and cetostearyl alcohol. An aqueous phase made up of sodium lauryl sulphate, Poloxamer® 407, propylene glycol, sucrose distearate and water in which micronised aciclovir had been hot(70°C)-suspended, was added to the oily phase. Addition was slow with continuous hot-stirring, and cooling to ambient temperature was allowed. The cream which formed was filled into 5-gram aluminium tubes internally coated with epoxy resin.
EXAMPLE 3
Aciclovir 5%
Sucrose 15% mono/distearate
Stearyl alcohol 5%
Cetyl alcohol 5%
Propylene glycol 15%
Brij® 721 2,5%
Brij® 72 2,5%
Mineral oil 5%
Stringy petrolatum 12.5%
Water q.s. to 100%
An oily phase made up of stringy petrolatum, mineral oil, cetyl and stearyl alcohol was prepared by melting at 60°C. An aqueous solution made up of Brij® 721 and Brij® 72, propylene glycol, sucrose mono/distearate and water in which micronised aciclovir had been hot(60°C)-suspended, was added to the oily phase. Addition was slow with continuous hot-stirring, and cooling to ambient temperature was allowed.
EXAMPLE 4
A formulation having the following composition was prepared:
Micronised aciclovir 263 g
Sucroester® WE 15* 750 g
Cetostearyl alcohol 338 g
Propylene glycol 1000 g
Sodium lauryl sulphate 37 g
Poloxamer® 407** 50 g
Mineral oil 250 g
Stringy petrolatum 625 g
Water 1700 g * Sucrose monopalmitate ** Copolymer of polyoxyethylene-polyoxypropylene
The ingredients of a fatty phase made up of stringy petrolatum, mineral oil and cetostearyl alcohol, were transferred into a Pressindustria-5L turboemulsifier. The temperature was brought to 60°C and the ingredients were allowed to melt for about 30 minutes. Water, sodium lauryl sulphate, Poloxamer® 407 were separately added into a 5-L dissolution tank and the mixture was heated to 70°C. After complete dissolution of the mixture, propylene glycol and sucrose monopalmitate were added and stirred for about 30 minutes at a temperature of 70°C. After achieving again complete dissolution, micronised aciclovir was added and suspended with stirring using an UltraTurrax® homogeniser, and a constant temperature was maintained. A 70 mmHg vacuum was created in the turboemulsifier and the turbine was started at 2800 rpm, stirring at 45 rpm. The homogeneous suspension made up of the aqueous phase at 65°C was slowly added to the stirred oily phase contained in the turboemulsifier, maintaining the temperature at 60°C, vacuum at 70 mmHg and stirring constant for 20 minutes. In the end cooling to ambient temperature was allowed for about 2 hours. The cream, with a homogeneous appearance, pH 7.1 and a viscosity of 12,000 cps, was filled into 5- or 10-gram tubes. EXAMPLE 5
A sample of cream containing 5% aciclovir marketed by Glaxo-Wellcome with the name Zovirax® Cream and having the following per-cent w/w composition:
Aciclovir 5%
Cetostearyl alcohol 6.75%
Propylene glycol 40%
Sodium lauryl sulphate 0.75%
Poloxamer 407 1 %
Mineral oil 5%
Stringy petrolatum 12.5%
Water 29.0%
was used a s a reference standard for permeation studies.
The cream described in Example 1 was compared with the above commercial cream Zovirax® using a percutaneous absorption apparatus (Crown Glass Company, New Jersey, USA) which uses continuous-flow Bronaugh cells to measure permeation through the skin of Guinea pigs (R. Bronaugh et al., Journal Pharmaceutical Sciences, 74, 64-67 (1985)).
The skin of Guinea pigs was mounted on Bronaugh cells having a surface of 0.3 sq.cm. to which an amount of cream equal to 200-250 mg was applied. A solution of phosphate buffer pH 7.4 was circulated for 48 hours and the various fractions were collected every 8 hours. The collected fractions were analysed by a reverse- phase HPLC method using a Waters-625 apparatus with a C18μ Bondapack column, injecting 20 μl, eluting with the mobile phase water:methanol:acetic-acid (840/160/1 ) at a rate of 1 ml/minute, determining absorption with a UV detector at 254 nm. The results of the permeation test are shown in Table 1 below: TABLE 1
Figure imgf000012_0001
It is obvious that the formulation in Example 1 could permeate through the skin layer in 48 hours an amount of aciclovir higher by at least 25% than the amount which was permeated by the commercial reference formulation Zovirax® 5% Cream. Based on this, the formulation which is an object of the invention allows improved drug permeation through the skin and induces improved drug absorption and, as a result, improved therapeutic efficacy.

Claims

CLAIMS 1. A pharmaceutical composition for the topical treatment of viral infections, comprising aciclovir, or any of its salts or esters, and a mixture of lipid ingredients in water, such composition containing from 0.1% to 40% w/w of a sucrose ester. 2. A pharmaceutical composition in accordance with claim 1 , characterised by he fact that the mixture is an emulsion made up of a lipid phase, an aqueous phase, emulsifiers and emulsion-stabilising agents. 3. A pharmaceutical composition in accordance with claim 2, characterised by the fact that the ingredients of the lipid phase are chosen from a group made up of linear or branched mono- or dialkylesters of fatty acid esters, mixtures of cetyl and stearyl alcohol and high-molecular-weight lipids. 4. A pharmaceutical composition in accordance with claim 2, characterised by the fact that the ingredients of the aqueous phase include a total amount of glycerine and propylene glycol lower than 30% w/w. 5. A pharmaceutical composition in accordance with claim 2, characterised by the fact that the emulsifiers and emulsion-stabilising agents are chosen from a group made up of cetyl alcohol, sodium lauryl sulphate, stearyl alcohol, cetostearyl alcohol, polyoxyethylene alkylethers and polyoxy stearylethers. 6. A pharmaceutical composition in accordance with claim 1 , characterised by the fact that the sucrose ester is a monoester of a fatty acid having an even number of carbon atoms. 7. A pharmaceutical composition in accordance with claim 6, characterised by the fact that the esterifying fatty acid is chosen from a group made up of myristic acid, oleic acid, palmitic acid and stearic acid. 8. A pharmaceutical composition in accordance with any preceding claim, comprising the following per-cent w/w ratios referred to the total weight of the composition: aciclovir, or any of its salts or any of its esters: from 0.1% to 10%; sucrose ester: from 0.1 % to 40%; water in admixture with a phase of oily ingredients: from 20% to 40%. 9. A pharmaceutical composition in accordance with claim 1 , comprising the following percent w/w ratios referred to the total weight of the composition: aciclovir (5%), sucrose monopalmitate (15%), cetostearyl alcohol (6.75%), propylene glycol (20%), sodium lauryl sulphate (0.75%), Poloxamer ® 407 (1 %), mineral oil (5%), stringy pertolatum (12.5%), water (34%). 10. A process for the preparation of the pharmaceutical composition described in claims 1-9, characterised by stirring: aciclovir or any of its salts or esters, a sucrose ester, the excipients making up the lipid phase and the excipients making up the aqueous phase in a turboemulsifier until a stable emulsion is obtained. 11. The use of a pharmaceutical composition in accordance with any preceding claim in preparing a medication useful in the treatment or prevention of viral infections caused by Herpes zoster, Herpes varicella and type-1 or 2 Herpes simplex.
PCT/EP1999/004606 1998-07-03 1999-07-02 Topical aciclovir formulations WO2000001390A1 (en)

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US11173209B2 (en) 2004-08-25 2021-11-16 Aegis Therapeutics, Llc Compositions for drug administration
US10576156B2 (en) 2004-08-25 2020-03-03 Aegis Therapeutics, Llc Compositions for drug administration
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EP1789075A2 (en) * 2004-08-25 2007-05-30 The Uab Research Foundation Absorption enhancers for drug administration
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US9763876B2 (en) 2008-03-28 2017-09-19 Hale Biopharma Ventures, Llc Administration of benzodiazepine compositions
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US20110245278A1 (en) * 2010-03-31 2011-10-06 Mustafa Nevzat Ilac Sanayii A.S. Compositions of opioid antagonists and methods for treating conditions caused by the varicella-zoster virus therewith
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AU2020286340B2 (en) * 2011-12-22 2022-12-08 Leica Biosystems Melbourne Pty Ltd Laboratory instrument control system
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GB201819418D0 (en) 2018-11-29 2019-01-16 Daniel Calladine Ltd Anti-viral compositions

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