ES2386943B2 - PHARMACEUTICAL COMPOSITION OF ACICLOVIR PROPHARMACES FOR TOPICAL USE. - Google Patents

Abstract

The present invention relates to a pharmaceutical composition of acyclovir prodrugs, which includes olive oil and a solubilizing agent, for topical use in the treatment of diseases caused by Herpes viruses. The prodrug used is an alkyl ester, such as acyclovir hexanoate, which can be obtained by esterification with an alkylamide and, more specifically, with N, N-dimertildecanoamide. Likewise, the invention relates to a method for obtaining the pharmaceutical composition, which comprises mixing an acyclovir prodrug with olive oil, adding a solubilizing agent and adding excipients suitable for a topical formulation.

Description

Pharmaceutical composition of acyclovir prodrugs for topical use

SUMMARY

The present invention relates to a pharmaceutical composition of acyclovir prodrugs, which includes olive oil and a solubilizing agent, for topical use in the treatment of diseases caused by Herpes viruses. The prodrug used is an alkyl ester, such as acyclovir hexanoate, which can be obtained by esterification with an alkylamide and, more specifically, with N, N-dimertildecanoamide. Likewise, the invention relates to a method for obtaining the pharmaceutical composition, which comprises mixing an acyclovir prodrug with olive oil, adding a solubilizing agent and adding excipients suitable for a topical formulation.

SECTOR OF THE TECHNIQUE

The present invention is part of the pharmaceutical sector. Specifically it refers to a new pharmaceutical composition for the treatment of Herpes virus.

STATE OF THE TECHNIQUE

The Herpes virus is a ubiquitous organism that causes infections in the human population of the entire world. Thus, diseases caused by Herpes viruses represent a major global health problem. Depending on the route of entry, Herpes viruses can be classified as: Neurotrophic (when infection in the human organism occurs through the nervous system) and Lymphotrophic, when the infection occurs at

through the lymphatic system Herpes simplex viruses (type 1 and 2: HSV-1 and

HSV-2) and Varicella Zoster (VZV) are framed within the

Neurotropic viruses, while human cytomegalovirus (HCMV), the

Epstein-Barr virus (EBV) and human Herpes virus (HHV-6, HHV-7 and HHV-8)

5

They are found within lymphotrophic viruses.

Acyclovir is a synthetic analogue of guanosine (2-amino-9- (2-

hydroxyethoxymetii) -3H-purin-6-one) that inhibits viral DNA replication, without

Affect the host. In terms of toxicity, acyclovir has demonstrated its

1 o

security for more than 30 years. However, the therapeutic success of

Acyclovir vs. HSV and VZV is limited by its low oral bioavailability

(15-20%) and its short plasma half-life (t1 / 2 = 2.5-3 hours). These two

factors have made it necessary to increase the oral administration dose of

acyclovir, as well as the frequency of administration, to achieve good

fifteen

clinical results Also, the low water solubility of acyclovir (0.2% at

25 ° C) is an inconvenience, because it makes the formulation of

preparations for administration, for example, by injections

intramuscular, such as ophthalmic eye drops (for ocular administration), or for

topical administration Topical administration is the most promising route

twenty

to administer acyclovir to patients. However, despite the

many efforts made in research, have not been achieved good

topical acyclovir formulations, because of the low solubility of

Acyclovir must be added the difficulty of acyclovir crossing the barrier

of the stratum corneum of the skin and reach the basal layer of the epidermis where it

25

Locate the viral infection.

In pharmaceutical technology, to overcome inconveniences of

bioavailability, stability, solubility, administration and others, a

alternative is the formulation of prodrugs, which implies modification

30

Chemistry of the pharmacologically active compound in a form

bioreversible that increases its therapeutic efficacy. An important aspect

   What should be considered in the formulation and synthesis of a prodrug is that

the alternative compound is toxicologically safe or acceptable. In the specific case of acyclovir, the synthesis of prodrugs is a particularly complicated issue. The use of solvents of the toluene type, DMF, or DMSO, allow to increase the solubility of acyclovir and accelerate the reaction rate to obtain the prodrug, but said solvents are toxic compounds that must be totally eliminated from the final composition. Recently, the inventors of the present patent application have presented an alternative and safe method of obtaining acyclovir prodrugs by esterification with alkylating agents in the presence of non-toxic solvents of the dialkyl amide group (EP2184286A1). Acidovir lipophilic prodrugs of the alkyl ester type, such as acyclovir hexanoate (ACVH), may be especially suitable for use in topical compositions such as gels and creams, because of their greater ease in crossing the skin and the considerable esterase activity of the epidermis However, the low solubility of ACVH can reduce the transfer of the active substance in the mixture itself, which can ultimately limit the effectiveness of acyclovir prodrugs for topical use.

From the above in this analysis of the state of the art, the need to have new compositions that have a greater capacity to transfer acyclovir prodrugs is readily observed, being especially interesting to obtain new compositions for topical use. The object of the present invention is to provide new acyclovir prodrug compositions for the treatment of Herpes virus topically.

EXPLANATION OF THE INVENTION

The present invention relates to a new pharmaceutical composition for topical use comprising a prodrug of acyclovir and olive oil. The method of obtaining said composition and its use for the treatment of Herpes viruses topically is also an object of the present invention. The mixture of an acyclovir prodrug, for example acyclovir hexanoate, with olive oil allows the prodrug to be solubilized so that better transfer values are obtained. Said mixture can be used to formulate more effective pharmaceutical compositions for the treatment of Herpes viruses, for example, for the formulation of topical compositions such as gels and creams.

In the context of the present invention, prodrug is understood as a compound that is obtained by reversible chemical modification of another pharmacologically active compound. Said prodrug has better properties for the preparation of pharmacological compositions or for the access and transfer of the starting pharmacologically active compound at the target site. In the context of the present invention, oil is understood as a water-insoluble fatty liquid that is obtained from vegetables, animals, minerals or by synthetic processes and which is mainly composed of triglycerides and glycerol. Olive oil means a vegetable oil extracted from the olive in which the major fatty acid is oleic acid.

The pharmaceutical composition object of the present invention comprises a binary mixture of: (a) olive oil and (b) mixture of solubilizers (said mixture of solubilizers being constituted by PEG40-Hydrogenated castor oil, polysorbate 20, octoxynol and commercially known water as solubilissant gamma 2429 and marketed by the Gattefosse house). In the present invention, the binary mixture is expressed in terms of the two ingredients that constitute it and several proportions are shown in Table 1. For example, in case 1, the binary mixture is 100% olive oil, but in the pharmaceutical composition olive oil accounts for 22.5%; in case 111, the composition of the binary mixture is 50% of each of the ingredients (a) and (b), so that each of them accounts for 11.25% of the pharmaceutical composition.

Table 1.

Ingredient

Quantity (g)

one

eleven 111 IV V SAW Vile VIII

Prodrug

0.50 0.50 0.50 0.50 0.50 0.5 0.5 0.5

Olive oil

4.50 - 2.25 1.13 3.37 2 1.6 2.4

Mix of solubilizers

- 4.50 2.25 3.37 1.13 2.5 2.9 2.1

Csp water

twenty twenty twenty twenty twenty twenty twenty twenty

Preferably

the proportion from the ingredients and (b) from the

5

binary mixture is comprised between the 25 and the 75% An elaboration

favorite

from the Present invention understands a mixture binary that

contains

a 44.44% from oil from olive Y a 55.46% from mixture from

solubilizers, so that, when preparing 20g of pharmaceutical composition

with 4.50 g of said binary mixture, a pharmaceutical composition is obtained

1 o

with a concentration of olive oil of 1.0%

Preferably

he prodrug from acyclovir that be It includes in the

Pharmaceutical composition object of the present invention

is found in

concentrations between 0.5 and 25% w / v, concentrations being more suitable

fifteen

between 1 and 5 or / op / v. In a particular embodiment of the present invention, the

Acyclovir prodrug concentration is 5% w / v. Preferably, the

prodrug

from acyclovir be It includes in the object composition from the

Present

invention is a ester from I rent from acyclovir Yet plus

preferably

saying ester from I rent be gets by a process from

twenty

esterification with an alkylating agent in the presence of an alkylamide according to

described in

EP2184286A1. In a particular embodiment of the present

invention, the acyclovir prodrug is acyclovir hexanoate,

and in a

realization

plus particular, saying hexanoate from acyclovir is obtained by

   esterification with N, N-dimethyldecanoamide.

In addition to a prodrug of acyclovir and olive oil, the new

composition for the topical treatment of Herpes virus object of the present

invention may include additional solubilizers of those available

commercially Preferably, the mixture object of the present invention

5

includes surfactants as a solubilizing element. In one embodiment

Particular of the present invention the solubilizer is a mixture of PEG40-

Hydrogenated castor oil, polysorbate 20, octoxynol and known water

commercially as solubilissant gamma 2429 and marketed by the house

Gattefosse Various excipients and compounds may also be included.

1st

pharmaceutically accepted and usually used for manufacturing

of creams, gels and, in general, topical pharmaceutical compositions.

Such excipients may include propylene glycol, alcohol

emulsifying ketostearyl, liquid paraffin, soft white paraffin,

petroleum jelly, poloxamer 407, methylparaben, propylparaben, water

fifteen

purified, etc.

Also the object of the present invention is the method of obtaining

a pharmaceutical composition for the treatment of Herpes virus that

comprises the mixture of an acyclovir prodrug, olive oil, a

twenty

PEG-Hydrogenated castor oil, polysorbate 20, octoxynol and mixture

water, excipients and water. Also the object of the present invention is the use

of a composition containing a prodrug of acyclovir and olive oil

as a medicine to treat Herpes virus. It is also an object

of the present invention the topical use of an emulsion-shaped mixture

25

o / w or gel containing a prodrug of acyclovir and olive oil.

DESCRIPTION OF THE DRAWINGS

As part of the specification, a figure is accompanied

30

(Figure 1) in which the assignment results are shown (ordinate axis in

milligrams per square centimeter) versus test time (axis of

   abscissa in hours) obtained for a commercial composition in the form of

cream (Aciclovir Pensa® cream EFG, Pensa Pharma SA), whose values are represented by filled squares, and for a composition object of the present invention (acyclovir hexanoate, olive oil, mixture of PEG-Hydrogenated castor oil, polysorbate 20 , octoxynol and water), whose values are represented by empty squares. With each value a vertical bar is shown that represents the variability of different replicas.

REALIZATION OF THE INVENTION

Specific examples of realization of the invention are described below with an explanatory and non-limiting nature.

Example 1: Procedure for obtaining a pharmaceutical composition of acyclovir hexanoate, olive oil (20%) and PEG40-hydrogenated castor oil in the form of an aqueous gel or hydrogel.

To obtain the pharmaceutical form, 5g of acyclovir hexanoate were added, 20g of olive oil and 25g of solubilissant gamma® 2429 (Gattefosse, France) were added consisting of a mixture consisting of PEG40-Hydrogenated castor oil, polysorbate 20, octocinol and water. Then, the whole was mixed with 50g of 1% Carbopol gel, which was made by dispersing 1g of Carbopol 940 in the necessary amount of milliq water for 1 OOg, allowed to hydrate for 24 hours and neutralized to pH 7 with triethanolamine. The final concentration of the drug in the developed gels was 5% w / w and that of 20% olive oil. The procedure gives rise to an aqueous gel or hydrogel that can be used for the topical treatment of herpes.

Example 2. Procedure for obtaining a pharmaceutical composition of acyclovir hexanoate, olive oil (16%) and PEG40-hydrogenated castor oil in the form of an aqueous gel or hydrogel.

It was carried out as example 1 but with 16g of olive oil and 29g of Example 5. Procedure for obtaining a composition

solubilissant gamma® 2429 (Gattefosse, France), final concentration of olive oil was 16%.

from way that the

5

Example 3. Procedure for obtaining a pharmaceutical composition of acyclovir hexanoate, olive oil (24%) and PEG40-hydrogenated castor oil in the form of an aqueous gel or hydrogel.

1 o

It was performed as example 1 but with 24g of olive oil and 21g of solubilissant gamma® 2429 (Gattefosse, France), so that the final concentration of olive oil was 24%.

fifteen

Example 4: Procedure for obtaining a pharmaceutical composition of acyclovir hexanoate, olive oil (20%) and PEG40-hydrogenated castor oil in the form of an emulsion o / w.

20 25

   To obtain this pharmaceutical form, 5g of acyclovir hexanoate was started, 20g of olive oil and 25g of solubilissant gamma® 2429 (Gattefosse, France) were added. Then, the whole was mixed with an emulsion made previously starting from 20g of petroleum jelly and 6.4g of polysorbate 80, which were heated to 70 ° C and mixed with 23.6g ultrapure water also at 70 ° C. When the emulsion reached a temperature of 40 ° C, the mixture of the drug with the solubilizing ingredients was incorporated. The final concentration of the drug in the dispersions developed is 5% w / w and that of olive oil is 20%. The procedure results in an emulsion of the type o / w that can be used for the topical treatment of Herpes virus.

Pharmaceutical of acyclovir hexanoate, olive oil (16%) and PEG40-hydrogenated castor oil in the form of an emulsion o / w.

It was carried out as example 4 but with 16g of olive oil and 29g of solubilissant gamma® 2429 (Gattefosse, France), so that the final concentration of olive oil was 16%.

Example 6. Procedure for obtaining a pharmaceutical composition of acyclovir hexanoate, olive oil (24%) and PEG40-hydrogenated castor oil in the form of an emulsion o / w.

It was performed as example 4 but with 24g of olive oil and 29g of solubilissant gamma® 2429 (Gattefosse, France), so that the final concentration of olive oil was 24%.

Example 7: Assay of cession of acyclovir hexanoate mixed with olive oil and PEG40-hydrogenated castor oil.

The transfer of acyclovir hexanoate of the pharmaceutical composition in the form of an emulsion or / w made according to Example 4 was compared with the assignment of acyclovir of a commercial composition in the form of cream (Aciclovir Pensa® cream EFG, Pensa Pharma SA) which It contains 50 mg of acyclovir per gram of cream, together with excipients (propylene glycol, Lanette wax, liquid paraffin, petroleum jelly, poloxamer 407 and purified water).

In vitro assignment tests of the active component were performed according to the recommendations established in SUPAC-SS (Guidance for industry for non-sterile semisolid dosage forms, 1997). Six Franz diffusion cells coupled to an automated Microette Plus® device (Hanson Research) were used. Polysulfone membranes (Tuffryn® Pall España SA) were used. The receptor medium was a phosphate buffer solution of pH 7.4. A volume of the receiving phase of 7 ml was used. The following sampling times were used: 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 and 24 hours. 1 ml of the receiving solution was taken at each sampling time, replenishing that same volume with fresh buffer solution. He

5 equipment was programmed to wash the tubes with 1.5 ml of phosphate buffer solution pH 7.4 before extracting each sample. The bath temperature (temperature of the receiving phase) was: 32 ± 1.5 ° C.

Based on the transfer results obtained, represented in the

10 Figure 1, a greater transfer can be observed from the product of the present invention than from the commercial preparation (Aciclovir Pensa® EFG cream).

Claims (7)

1. Pharmaceutical composition comprising an acyclovir prodrug, 5 olive oil, a solubilizing agent, water and adequate amounts of excipients to constitute a topical formulation. 2. Pharmaceutical composition according to claim 1, wherein the Olive oil concentration is between 0, 1 and 25% w / v and the 1 O concentration of acyclovir prodrug is between 0.5 and 25% w / w. 3. Pharmaceutical composition according to claim 2, wherein the concentration of olive oil is between 15 and 25% w / v and the concentration of the acyclovir prodrug is between 1 and 5% w / v. 4. Pharmaceutical composition according to claim 3, wherein the concentration of olive oil is 20% w / v and the concentration of the acyclovir prodrug is 5% w / v. The pharmaceutical composition according to any of the preceding claims, wherein the acyclovir prodrug is an alkyl ester. 6. Pharmaceutical composition according to claim 5, wherein the Acyclovir prodrug is an alkyl ester obtained by esterification with an alkylamide. 7. Pharmaceutical composition according to any of claims 5 and 6, wherein the acyclovir prodrug is acyclovir hexanoate. 8. Pharmaceutical composition according to claim 7, wherein the acyclovir prodrug is acyclovir hexanoate obtained by esterification with N, N-dimethyldecanoamide.

5

9. Pharmaceutical composition according to any of the preceding claims, wherein the solubilizing agent is PEG40-castor oil hydrogenated with polysorbate 20, octocinol and water. 1O. Pharmaceutical composition according to claim 9 wherein the concentration of the solubilizing agent is between 20 and 30%.

1 o

11. Pharmaceutical composition according to claim concentration of the solubilizing agent is 25%. 1 or in the that the

fifteen

12. Pharmaceutical composition according to any of the preceding claims, which includes one or more excipients selected from propylene glycol, emulsifying ketostearyl alcohol, liquid paraffin, soft white paraffin, filament petrolatum, poloxamer 407, methylparaben, propylparaben.

twenty

13. Method of obtaining a topical pharmaceutical composition comprising the steps of mixing an acyclovir prodrug with olive oil, adding at least one solubilizing agent and adding one or more suitable excipients for a topical formulation.

14. Use of a pharmaceutical composition as defined in any one of claims 1 to 12, or obtained according to the method defined in claim 13, for the treatment of Herpes virus topically.