SA99200836B1 - Antiviral formulations include propylene glycol and isopropyl alkanoic acid ester. - Google Patents

Abstract

Abstract: A topical compound composed of an anti-inflammatory glucocorticoid and a nucleoside analogue antiviral agent in a drug carrier characterized by the fact that the carrier consists of about 15 to about 25% by weight of propylene glycol and from about 10 to about 25% by weight of C12-C22. isopropyl alkanoic ester. This compound has an effect in the treatment and prevention of infection with the herpes virus, and it is distinguished by its antiviral effect and its therapeutic effect, and we have a long shelf life for use.,

Description

. TT and propylene glycol ester Contains antiviral formulations Antiviral formulations isopropyl alkanoic acid ester Full description Z Background of the invention It uses antiviral formulations The invention relates to topical antiviral formulations Sle lea is an antiviral Sle for oral or genital route and includes 0 or prevention of herpesvirus. 4 YE veo The international patent No. describes an anti-inflammatory in an acceptable carrier glucocorticoid for viruses acceptable for topical and pharmaceutical use. The carriers disclosed herein include conventional formulations of each of the corresponding active substances; In the sense that a traditional antiviral formulation was mixed with a formulation, and these mixed formulations had a large number of components with the presence of . glucocorticoids - the potential for these components to interact with each other endogenously; Which leads to a kind of instability and unknown physico-chemical properties European Patent No. 44057 relates to oil-in-water formulations and indicates that an effective topical invention requires © acyclic nucleoside antiviral agent acyclovir by weight on 0 The load is at least 77.0 of its weight; It is preferable that Bll include 1

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Least fat glycol 1606 no 0100. This combination clarified the structure of MAC and formed the basis for the most marketable of topical cyclovir preparations. The international patent application No. 1117/1 relates to topical formulations of oil in L.L.) or topical aqueous formulations of a non-acyclic nucleoside antiviral substance, penciclovir. And these formulations must include not less than JT of 0 weight; preferably, they contain no less than 73% of propylene glycol by weight. European patent application No. 4 £11 relates to topical formulations of penciclovir, which includes 770 by weight. Propylene glycol and an emulsifier is decyl methyl sulfoxide. As for the international patent application No. 0 M4, it relates to topical formulations penciclovir penciclovir containing not less than 770 by weight and preferably not less than 38 by weight of propylene glycol and an emulsifier of 1000 -cetomacrogol. As for the formulations of a mixed product that includes a component A strongly lipophilic component such as hydrocortisone and a lipophobic component such as an acyclic nucleoside analogue are difficult in the case of conventional drugs; But it is more difficult in the case of topical preparation, where Yo must take into account the release rates of the active substances to the target part of the tissue. And as described in the publications mentioned in the previous two paragraphs; Until now, it had been necessary to use a high level of propylene glycol when forming an acyclic nucleoside analogue to reach an appropriate penetration of the antiviral substance into the skin or mucous membranes. We have discovered, however, that while conventional carriers can be used, a higher concentration of propylene glycol 0 can be used to prepare effective antiviral formulations within the scope of the previous international patent Ave.

M. This No. 11/7 (any formulations including a glucocorticoid and an antiviral substance) ¢ These conventional carriers lead to a short-lived product on storage that is neither an ideal antiviral nor an ideal in terms of its therapeutic performance. ° According to the invention; A combination as defined in claim 1 is provided. In the context of the invention, “this blending of low concentrations of propylene glycol with an alkanoic acid ester isopropyl alcohol allows good penetration and release of the antiviral component” while avoiding; At the same time ; Instability exhibited by conventional antiviral formulations. The compounds of this invention are useful for the treatment or prevention of diseases caused by members of the herpes virus family 0 (Lahla). Such as type 1 herpes simplex (orofacial infection in most cases) + or type ¥ of herpes simplex (genital infection often) 0 and primary infection with varicella virus zoster (chicken pox) and secondary infection (shingles; and Forms No. 6” and No. 4 of herpes virus (interspersed in the skin in the case of Kaposi's sarcoma 0.0 and the like) include prophylaxis in the context of this invention Preventing infection (including preventing spread to nearby healthy tissues) and preventing reactivation of previous infection with the herpes virus, such as reactivating herpes dormant in 0 neural tissue. Topical treatment or prevention of herpes virus infection in humans M5

Especially type 1 of herpes simplex and type 1 of herpes Ld. As for the weight percentages here, they refer to the weight of a component in relation to the total weight of the formula. and to select aa ; Preferred antivirals include penciclovir; 4hydroxy-2-(hydroxymethyl) butyl] guanine (hydroxymethyl) butyl] guanine (H2G) -9 °, especially acyclovir . And the antiviral substance can be in the form of an ab prodrug that is assimilated in the same place; with epidermal esterases or xanthine oxidases; To form an antiviral substance, as previously mentioned. The antiviral substance in the formulation is present in quite typical concentrations of the corresponding nucleoside; from 1 - a 7 wt such as to range around ; and © 7 wt. Among the things with 0 advantage; That the composition is saturated to a large extent or completely saturated with the antiviral substance. The glucocorticoids in the formulation are present in concentrations quite typical for the corresponding glucocorticoids; As its concentrations are well known in the field of glucocorticoids and are generally located in the range from 1.1 to 701 by weight. and for example ; the composition may include from 011 to 0 by weight and preferably from 400 to 77 by weight; Such as containing about 21 Vo by weight 'hydrocortisone' and both glucocorticoids and antiviral components can be in a completely soluble form according to the type of carrier; but they attend Lads; of a raw material having a micron-grain size, such as those having more than V0 and preferably more than 790; Its particles are less than a specified particle size. For example, glucocorticoid mm is prepared

- hydrocortisone from a raw material with aaa granules less than µm and traditionally » penciclovir 0 acyclovir with a granule size less than VO µm is provided; Less than 1 micrometer is preferred. The compositions of the invention are biphasic and include two separate oily and aqueous phases; Either in the form of an oil-in-oil emulsion “and it is preferable that the composition include a dispersed oil phase and a continuous aqueous phase, and it is preferable to have isopropyl alkanoic acid ester and lipophilic glucocorticoid hidden in the oily phase 0, while the antiviral nucleoside will exist as dale in the aqueous phase 0, specifically in combination with propylene glycol. Ve The components of the oil phase may include conventional fats and oils and their esters; Such as those found in the European Pharmacopoeia and other constitutions ‎European and other pharmacopeaias It is preferable that the components of the oily phase are not lubricated; It is non-staining and can be washed. The traditional pharmaceutical components of the oily phase include mineral oils such as liquid paraffin, vaseline and the like. Jie alkanoic acids stearic acid and fatty alcohols such as cetostearyl alcool; Straight or branched chain mono- or dibasic for alkyl esters such as isocetyl stearate 5 « di-isopropyl adipate © and propylene glycol diester for fatty acids extracted from coconut «coconut» and decyl oleate 6, 2-ethylhexyl palmitateY 5 « butyl stearate and AY! stearate — 2-ethylhexanoic acid and the like 0 Ale |

vy - — and the isopropyl esters preferred to the alkanoic acid esters include the dodecanate “0 eicosanate or behenoate esters” stearate “palmitate” myristate especially isopropyl .myristate and the composition of the invention includes about 10 to 778 by weight isopropyl alkanoic acid ester «and it is preferable to include about 11 to IVA by weight such as to include about 715 by weight. The composition of the invention includes about VO to about 775 wt. The concentration of propylene glycol is about 0 by weight, as this concentration secures; in general ; Good preservative effect without the need for exogenous preservatives in the formulation 0.01 and traditionally the 0 formulation of the invention contains an emulsifier (surfactant); in an amount from exactly 1.06 to 78 by weight; Preferably, it should be from 1.1 to 71 by weight. The European Pharmacopoeia describes a number of pharmaceutically acceptable emulsifiers, including nonionic, cationic, and non-ionic emulsifiers. Examples of non-ionic emulsifiers include cetomacrogols such as 1000 ccetomacrogol ethylene or glyceryl esters s diethylene glycol monostearate behenate, oleate and stearate, etc. 0 and J compounds——is laureth compounds lauromacrogols in macrogol monomethyl ethers and mono-and diglycerides ¢ and poloxamers 4 octoxinols s nonoxinols such as 407 poloxamer and polyoxyl castor oils « and polyoxyl stearates » and polysorbates ¢ and propylene glycol 5 « polyvinyl alcohols Avo

M-28 + and sorbitan esters and the like, preferably Poloxamer 188 as a nonionic reducer for surface tension 0 surfactant. Examples of anionic emulsifiers include aluminum monostearate - anionic emulsifiers, calcium stearate, and sulphated castor oil. ; And magnesium stearate and pendecamaine ¢ and sodium oleate © and sodium stearate and sodium stearyl fumarate i.e. sodium tetradecyl sulphate + and zine stearate and the like. One of the preferred anionic emulsifiers is sodium lauryl sulphate. The composition of the invention may include conventional auxiliary materials such as surface anesthetics. sunscreens ¢ and flavorings; scents); emollients, skin tone colourants, and masks. The invention formulations can be prepared by traditional mixing methods. It is preferable to prepare the formulations by conventional two-phase mixing methods; Where the two phases of oil and aqueous propylene glycol are mixed separately, and a homogenization is made for them, while their temperature is set to be normal before mixing. 1 The active ingredients (i.e., glucocorticoid) nucleoside analogue may be added to their corresponding oily and aqueous phases before or after mixing. It is preferable, 0, for the purposes of minimizing recrystallization, that the active ingredients be added after mixing the two phases. This means that an increase in volume occurs when the active ingredients are added, in addition to that the two-phase mixture is generally at a lower temperature.

As for viral images (diel); such as herpes simplex on the lips and/or genitals; Herpes zoster (shingles) is casual. With all antiviral therapies, it is desirable to start treatment as soon as possible after reactivation of dormant herpes infection and the onset of an effect is or is suspected.

and for example ; Many people experience a slight warmth or tingling at the point where the effect will occur a day or so before they recognize the visible symptoms of herpes. Preferably, the composition of the invention should begin to be used at this point. In some patients, exposure to some stimuli such as ultraviolet radiation while skiing or from the tropical sun; as well as harsh emotional stresses; menstrual periods; It can cause reactivation of herpes in certain areas.

0 And the composition of the invention can be used in a preventive manner when exposed to these influences and in any of these two situations. Accordingly, it is desirable for the composition of the invention to withstand a long storage period outside the refrigerator; So that the medicine can be saved at home or

at work and/or while traveling. Vo, and the formula can be used in general to treat primary or obvious infection from two to 1 times a day during exposure, i.e. by using it every three hours, for example. It is preferable to continue using it until reaching the hard crust stage at least, which usually takes from? Up to 10 days from the start of feeling the expectation of exposure 0. It is preferable that the invention formulation be presented in a tube containing from 175 to 50 ml. 0 And the tube contains - traditionally - a quantity sufficient to treat a severe cold or one injury in the organs (Avo).

11. = - genital; Like from 1 to #ml . This will allow use several times daily for a period not exceeding a week or ten days; excluding the remaining quantity; Thus, the possibility of contamination of the open tube and/or cross-infection between individuals sharing the same tube can be minimized. As for efficacy studies before the clinical examination regarding the composition of the invention, it can be evaluated as shown in the examples or by the method of transmission followed for the immunity model described in the two international patents No. 4785 336/7 and 37 52/144. Brief explanation of the drawings Different models of the invention will now be illustrated by way of an example only and by reference to the following examples and shapes, which do not limit the scope of the invention, namely: topically with the composition of the invention or with a formulation without the active substance; Figure ?: Histogram of incidence versus time for herpes-infected guinea pigs treated topically with a conventional carrier or an inactive formulation; 0 Fig. ?: ily plot to record infection against time for guinea pigs infected with herpes ils, treated topically with a formulation outside the scope of the invention or a formulation devoid of the active substance; Fig. tf An accurate image showing the growth of a crystal in a conventional formulation 0 Fig. ©: An accurate image showing the lack of crystal growth in a formulation of this invention. Mahm

11 - FIGURE 1: ILY graph of infection-recording against time for guinea pigs infected with herpes and treated topically with the invention formulation or a formulation prepared according to the international patent 47805 476/7; example; Figure 7: Graph of incidence versus time for guinea pigs infected with herpes ° and treated topically with a formula synonymous with the invention or with a formula prepared by the method of Able International Patent 37/747806. Detailed description A composition was prepared according to this invention from the following ingredients: Example 1 0 oil phase: 1,0 cetostearyl alcohol 1 gram Vaseline 5 grams TY, 0s liquid paraffin 5 grams foo isopropyl myristate 5 grams Yo, 0 aqueous phase :- vu propylene glycol grams ARIE Lah Marg 0 A sodium lauryl sulphate poloxamer 188 grams ZY , eA aq. purif gram IY 6A Ave

117 - active components: - ee acyclovir 86 grams (ZY, ala), es hydrocortisone, and the particle size of acyclovir (Recordati micronised.

USP 23/BP 93 /Eur ph 111) ° SY lit, 50% = 4tm, 90% = 7 lim & 100% = | 5 pm 2 = 10% hydrocortisone (Pharmacia & Up John micronised USP/EP/BP) 0 had jum, geometric mean diameter 2 pm 5 > 10096; The used purified water was treated by the reverse osmosis method, 0 TeVerse 0Smosis, and the components of the oil phase and the aqueous phase were placed in their mixing vessels; They are heated to Ve with stirring. And when the two phases are at the same two temperatures; 1 The oily phase is poured onto the aqueous phase from the top with continuous stirring for a period from © to Foo at the maximum possible speed so as to avoid drawing air into the mixer. The emulsion prepared in the previous way is homogenized and then cooled. by continuous stirring; until a temperature of vv to yo mm 0 then the active ingredients are added and stirring continues until the active ingredient is wetted and mixed. Ave

DDS - After that, a second homogenization process is carried out for the mixture and it is cooled until it has a consistency like that of an orca, and its temperature is approximately 1 °C before it is messed up. Example 1 Then preparing a penciclovir/hydrocortisone formula according to this invention from the following ingredients: Oil phase: Cetostearyl alcohol 0 grams of Vaseline 0.0 grams of ZY liquid paraffin 58 grams z/o,M0 vs isopropyl myristate 0 grams Yo, aqueous phase :- vs propylene glycol grams Ya, AN sodium lauryl sulphate grams La As poloxamer 6 g ZY, 0s A aq. purif 01 gram IY E,A active ingredients :- penciclovir 70.44 gram hydrocortisone 6 gram ZN, Ate

14 — - As for ana hydrocortisone particles (Pharmacia & Up john micronised USP/EP/BP), it was as follows: ‎m, geometric mean diameter 2 jj. m.5 > 100% ° and the purified water was treated by reverse osmosis. Penciclovir was crushed to a mean diameter of µm. The components of the oil phase and the aqueous phase are placed in their respective mixing vessels; Then they are heated to 17°C with stirring. And when the two phases are at the same two temperatures; The oily phase is poured onto the aqueous phase of the Jel, while stirring continues for a period of 0 to 0 minutes at the maximum speed possible so as to avoid drawing air into the mixer. The emulsion prepared in the previous way is homogenized 008 and then cooled; by continuous stirring; Up to a temperature from © to YO 2, then the active ingredients are added and the stirring continues until the active ingredient is wetted and mixed. After that, a second homogenization process is performed for the mixture and it is cooled until it becomes creamy. Its temperature is approximately 1 SY before being packaged. Comparative Example 1 The acyclovir/hydrocortisone composition was prepared using the prior art MAC carrier described and protected by EP No. 454 of the following ingredients = Ale

~ and 1 - shall oil phase :- Je al_arYive cetostearyl alcohol vaseline 5 grams es for al aYA Yo liquid paraffin 10,10 © aqueous phase :- 1 propylene glycol g mm sodium lauryl sulphate 5 g 7A poloxamer 5 g ZY, 0s aq. purif 7 grams of AEWA 0 active ingredients: - Acyclovir, Lm 8, Hydrocortisone 7 grams, ZY, and the ingredients have been mixed exactly as explained in example 1. Comparative example 1 1 A compound cyclovirhydrocortisone uses a low concentration of propylene glycol (PG) (relative to the MAC formulation of the previous invention) but without the isopropyl alkanoic ester (IPM) of the compound according to of the present invention was prepared from the following components: ‎Ave

11 - Oil phase: Cetostearyl alcohol 7.0 grams Vaseline 6 grams Yas liquid paraffin 5.6 grams 88 0 Aqueous phase aqueous phase: Propylene glycol 1 g AL sodium lauryl sulphate g vA ZY, ala, es poloxamer 188 Purified water 8 1€6,A al af 0 Active ingredients: - Acyclovir g M 8 ZY, Alay, en Hydrocortisone The ingredients were mixed exactly as explained in Example 1 Biological Example_ a of sll \ M The effectiveness of the compounds as antivirals according to the invention and the comparative examples; 145 Alenius et al, J.

Inf, Dis, (1982) 573 - 569). 1 hour of inoculation; Aveo samples

117 - For the test and treatment without the active substance, it was swabbed on the places where the herpes infection began. This topical treatment was repeated twice daily for ? or; days. The sites of infection were counted daily, and the infection was estimated in a number of animals. Y represents a number of injuries, some of which are clustered. “» - represents the best development in the clustered injury sites. Figure 1 shows the results of a compound according to the invention (Example 1) compared to a therapeutic compound without the active substance (a MAC compound similar to Comparative Example 1; but without the active ingredients) which results in 0 non-inhibition of bacterial growth. Figure 1 shows a compound of a previous invention (comparative example 1 - acyclovir and hydrocortisone in a MAC compound) compared to a treatment without the active substance. Figure 1 shows a compound outside this invention (comparative example 1 low) IPM JPG Compared to treatment without the active ingredient Referring to the formulations that do not contain the active ingredient, it is clear that in the absence of antiviral vo and glucocorticoid, severe infections occur within * days and remain unhealed for more than + days. Interferon / 10 according to the aforementioned international patent 455 176/7 (comparative example 1) was newly produced (freshly) and consists of a nucleoside analogue and an anti-inflammatory glucocorticoid in the Gale MAC compound. This combination achieves a slow improvement in Ave ‏

1 - Severe infections (from day 1 to 0) and a small amount of infection (maximum amount of infection? on day 6). As indicated by ISBN 47508 476/7, these formulations are useful in the treatment and prevention of herpes infection. Generally As illustrated in the laboratory test in Example 1, this MAC formulation is not commercially viable in combination therapy regimens.

0 With reference to the comparative example in Figure 7 and as expected according to what is contained in the European patent ?7,56;? Patent 111789/41, EP 774 496, and International Patent for Multiple Appearances and Applications of the MAC formulation; With a reduction of the propylene glycol level to less than “at least ¾ percent by weight” as indicated by these patents, which thus leads to a decrease in the efficiency of virus resistance and results in a slightly (marginally) better formulation

0 than those without the active ingredient. Especially since the amount of infection is less by half a unit than that resulting from treatment with the compound devoid of the active substance, with a slight decrease in the time until the occurrence of infection and the time until recovery.

On the contrary, the compounds according to the present invention shown in Figure 1 are shown

A clear improvement in both the treatment without the active substance and in the formulation of the invention

vo as shown in Figure 7. Especially since the injury record always remains less than 1 and reaches less than 8 per day + .

It has become clear that a formula containing a low concentration of propylene glycol with

The addition of isopropyl alkanoic acid ester and isopropyl myristate clearly increases the efficiency in

Treatment and viral resistance of a group of products including interferon and glucocorticoid

,. Anti-inflammatory 0

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and 1 - Figure 1 shows the infection history as a function of days in the guinea pig model, as previously shown by Las, but with the use of a slightly more virulent type of herpes simplex virus type 1; Through an experiment by comparing the compound according to the invention (Example 1) with a compound that also contains hydrocortisone and acyclovir but prepared according to Example ¥ of the private international patent application Ly No. M11/747585. It will be shown that both compounds achieve a good degree of healing, but the compound according to the present invention has a better effect on the more severe injury at the early infection. When tracking the disappearance of the injury (in the figure), we find that the area under the curve of the boat according to the present invention is less by about 0 than that of the boat according to the previous invention. Figure 1 shows the injury log as a function of days for the guinea pig model 0 shown in Figure 1. The result of an experiment by applying his cream according to the example? Contains the antiviral penciclovir and glucocorticoid hydrocortisone For the purpose of comparison the cream was prepared in a manner similar to the method described in our International Patent Application 495056 456/7 using commercially available Denavir® (penciclovir) from SmithKline Beecham Corporation in PHOTOS OF CREAM AND 196 ACO Hydrocortisone The compound according to the present invention achieves a significantly less severe injury record. 1 Figure Lad V shows the results for experimental animals treated with the inactive compound. Example Test 1 Figures; and © are X£0 magnified photomicrographs of the compound which shows the composition according to the previous invention (Fig.; Jia comparative 1) and the composition according to the present invention (Fig. Jaco 0) (Ate vy. in Op Referring to Figure © which shows the composition according to the present invention after It shows that 7107 crystalline and pellets of the 0°C phase for six months 0°C oily temperature are completely dispersed in the aqueous phase.The manifestations of this compound after six months From storage identical: Exactly to that when it was newly produced

° On the contrary, Figure 4 shows an enlarged composition 5607 consisting of a glucocorticoid and an antiviral nucleoside analogue in a carrier manufactured according to previous techniques, specifically containing about 6 by weight of propylene glycol. When prepared recently, it was not possible to differentiate microscopically between this composition and that shown in Figure ©. In general, after storage for? Months and © weeks at a temperature of Yo 5 shows the growth of needle crystals in this composition of previous techniques.

0 The analysis showed that these needles consist of the hydrocortisone component of the formula, which was deposited from the solution in the oily phase; Which led to the availability of reasonable amounts of this juice in the formula. It is also evident that the oily phase is less diffuse than the micrograph in Figure 0.

Although the invention is illustrated with reference to specific and proposed embodiments of the antiviral agent cyclovir yg ¢ and ..isopropyl alkanoic acid ester [PM . it is worth

Vo taking into account that this invention is not limited to what was mentioned in the previous text, but rather extends to the spirit and scope of the attached protection elements.

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Claims (1)

71 - lead elements 1-1. Topical compound in the form of an oil in water emulsion to include 211 =o) (w/w) hydrocortisone 1-NO2 (wt). / wt) ¥ of an antiviral nucleoside analogue chosen from cyclovir ¢, penciclovir, or 4hydroxy-2-(hydroxymethyl) butyl] guanine(hydroxymethyl) butyl] guanine ° -9 1 In a drug carrier comprising propylene glycol and 0l isopropyl Ci; - Cp, alkanoic acid ester characterized by Ob the carrier includes from 711 - 4 775 by weight (with respect to the total weight of the composition) of propylene glycol and from 701 = 715 by weight of alkanoic acid ester 4 without - bin 0 isopropyl 1 "- - the compound according to claim 1 where the support material consists of 218 - 7277 Y by weight and preferably about 771 (w / w) of 'propylene glycol D 0 *- _The compound according to claim 1, where the support material consists of 719 = 7148 by weight Y, preferably about JAY: by weight of -1sopropyl alkanoic acid ester (Sd) — 1 according to the claim "where isopropyl alkanoic is chosen acid ester of Y: dodecanate esters group, myristate, palmitate, stearate, alkanoic, behenoate 1, or a mixture thereof. —o 1 Compound of the claim; where isopropyl alkanoic acid ester is nad - myristate isopropyl Y is the nucleoside analogue of any of the preceding claims, since the compound Els - 1 0 acyclovir Y acyclovir has a composition of 4-77 by weight Cum 1 Alan] “7-_ the compound according to element 1 0 hydrocortisone by weight of ZY - + 0 7 by weight of ZY - 1 where the composition includes 1 +-_ compound of claim 1 -hydrocortisone by weight of 77 - .,5 se AY - 1 penciclovir Y It is used in the manufacture of a drug for the treatment or prevention of 1 compound according to claim 4-1 and where the drug is formulated for current administration.