WO1993012766A1

WO1993012766A1 - Microemulsion excipient for a suppository and method for producing same

Info

Publication number: WO1993012766A1
Application number: PCT/FR1992/001114
Authority: WO
Inventors: Guy Vergnault; Nabil Farah
Original assignee: Gattefosse S.A.
Priority date: 1991-12-31
Filing date: 1992-12-01
Publication date: 1993-07-08
Also published as: FR2685636A1; FR2685636B1

Abstract

An excipient (1) for a pharmaceutical suppository is described. The excipient includes a mixture of at least one hydrophilic liquid phase representing at most 5 % wt of the microemulsion; at least one lipophilic phase consisting of a solid mixture of glycerides and making up 30-70 % wt of the microemulsion; at least one polyethylene glycol-based short-chain surfactant and at least one polyglycerol-based cosurfactant which together make up 30-50 % wt of the microemulsion. A method for preparing the suppository is also provided.

Description

EXCIPIENT FOR SUPPOSITORY CONSISTING OF A MICROEMULSION AND METHOD FOR MANUFACTURING THE SAME.

The invention relates to a pharmaceutical suppository excipient consisting of a microemulsion; it also relates to a process for manufacturing it.

As is known, a "suppository" is a drug of solid consistency, which melts at the temperature of the human body and which is intended to be administered by the rectum. Essentially, a suppository comprises a solid excipient which, as already said, melts at the temperature of the human body, impregnated with the active principle or principles which it is desired to administer. A suppository is normally administered in a single dose, for local action or a systemic effect. This form of medication provides rapid and excellent bio¬ availability. By the addition of adjuvants, one can play on the viscosity of the excipient, which makes the active product more or less bio-available.

For the production of suppositories, a solid excipient compatible with the human body is therefore sought, capable of retaining the active ingredient (s), of melting frankly at the temperature of the human body, in order to be able to assume excellent bio-availability and / or a prolonged effect.

The absorption by the human body of the active ingredients in aqueous solution generally occurs rapidly. However, from suppositories, this absorption is generally slower, because it depends on the nature of the excipient, the formulation additives, as well as the physico-chemical characteristics of the active principle. The amount of water present in the rectum is generally low, that is to say less than two milliliters, which therefore does little to promote solution of the active ingredient. The rapidity with which the active substances are released from suppositories and are absorbed by the rectal mucosa, is therefore directly linked to the solubility of the active principle in the excipient. In other words, the speed of diffusion is linked to the partition coefficient of the active principle between the excipient and the rectal liquid. The active ingredients which are very soluble in the excipient diffuse much less easily than those which are insoluble or poorly soluble, and consequently are much less absorbed.

The invention solves this problem. It relates to an excipient for a pharmaceutical suppository, constituted by a solid microemulsion, comprising in mixture:

. at least one hydrophilic liquid phase, chosen from the group comprising water, alcohols, polyols, glycerol, alone or as a mixture;

. at least one lipophilic phase consisting of a mixture of glycerides; . at least one short chain surfactant based on polyethylene glycol; . at least one co-surfactant based on polyglycerol.

This excipient is characterized in that:

- The lipophilic phase is solid and represents from 50 to 70% (fifty to seventy percent) of the weight of the microemulsion; - the hydrophilic phase represents at most 5% (five percent) of the weight of the microemulsion;

- The mixture of surfactant and cosurfactant represents from 30 to 50% (thirty to fifty percent) of the weight of the microemulsion. As we know:

- a "microemulsion" is a homogeneous, fluid and stable solution, composed of four major constituents, respectively a hydrophilic phase generally of water, a lipophilic phase here solid, at least one surfactant (TA) and at least one co-surfactant (CoTA);

- A "surfactant" is a chemical compound having two groups, the first polar or ionic short, which has a great affinity for water, the second which contains a more or less long aliphatic chain and is hydrophobic; these chemical compounds with a pronounced hydrophilic character, are intended to cause the formation of micelles;

- A "cosurfactant", also sometimes called "cosurfactant", is also a chemical compound, but more hydrophobic in nature, intended to cause mutual solubilization of the aqueous and oily phases in a microemulsion.

For the most part, microemulsions have been widely studied for the recovery of petroleum. It is therefore unnecessary to describe them here in detail.

In document EP-A-0 334 777, the Applicant has proposed using these microemulsions in the pharmaceutical industry. But here, the mixture of surfactants and co-surfactants is less than thirty percent (30%), the lipophilic phase, always oily and not solid, represents at most fifteen percent (15%) and the hydrophilic phase (water) represents thirty percent (30%) or more of the weight of the microemulsion. In other words, the invention relates to a suppository excipient, formed by a microemulsion, the lipophilic phase of which consists of a mixture of saturated glycerides which represents from 10 to 70% (ten to seventy percent) of the weight of microemulsion. This microemulsion is in solid form at room temperature, but melts or dissolves frankly at the temperature of the human body, which advantageously makes it possible to release the active principle or principles retained by the excipient with, in addition, the possibility of 'a prolonged effect more and more sought after.

Advantageously, in practice:

the hydrophilic phase is chosen from the group comprising water, ethanol, propylene glycol, isopropanol; advantageously, water is used in an amount of 0.5% by weight of that of the emulsion; this hydrophilic phase essentially makes it possible to form the microemulsion; in this way, an amount of water of the order of 0.5% is considered most generally satisfactory; in a variant, the hydrophilic phase, which is very minor, can be provided in situ at the level of the rectum, by the rectal liquid itself; the microemulsion is then formed when all the elements are combined in the liquid state in the rectum;

the lipophilic phase which essentially makes it possible to dissolve an appreciable part of the active principle, consists of a mixture of mono-, di- and saturated or even unsaturated triglycerides; preferably, this mixture of saturated glycerides is richer in triglycerides than in diglycerides, and richer in diglycerides than in monoglycerides; preferably, the mono, di and triglycerides are hemi-synthetic glycerides of saturated Cs-Cis fatty acids, of the type sold by the Applicant under the registered trademark "SUPPOCIRE DM"; - In a variant, these saturated glycerides are associated with polyoxyethylenated fatty esters of the type of those sold by the Applicant under the registered trademark "SUPPOCIRE CS2X";

in another embodiment, the lipophilic phase consists of saturated polyglycolysed glycerides, of the type of those marketed by the Applicant under the brand "SUPPOCIRE CP";

- The lipophilic phase represents approximately 50 (fifty) to 55% (fifty five percent) of the weight of the microemulsion;

- the surfactant (TA) is coester in Cβ-Cio of glycerol and polyethylene glycol of average molecular weight close to 400, such as that marketed by the Applicant under the brand "LABRASOL", and the co-surfactant (CoTA) is an ester of a liquid fatty acid, such as oleic acid or isostearic acid, and of a polyol of molecular weight between 100 and 1000.

The invention also relates to a method for preparing a suppository for pharmaceutical use from an excipient consisting of a microemulsion described above. This process consists of:

- First, to melt by heating the mixture of saturated glycerides characteristic of the invention;

- Then, to maintain this mixture in fusion while bringing the temperature between 30 and 35 ° C;

- Then, with gentle stirring at a temperature always between 30 and 35 ° C, to add a mixture of surfactants, cosurfactants and active ingredients;

- then, to add to this molten mixture at most 5% (five percent) by weight of water;

- Finally, homogenize this mixture, then pour it in the form of suppositories, which is removed from the mold after cooling. The manner in which the invention can be implemented and the advantages which result therefrom will emerge more clearly from the exemplary embodiments which follow.

In all the examples, unless otherwise indicated, the lipophilic phase consisting of the mixture of saturated glycerides characteristic of the invention is first melted in a water bath by heating at 60 ° C. The supercooling is maintained by reducing the temperature of the molten oil to 30-35 ° C. and the active principle is added to it.

Then added to this melted oil, with gentle stirring, always at a temperature between 30 and 35 ° C, the mixture of surfactants and cosurfactants, then the appropriate amount of distilled water.

A translucent microemulsion at 35 ° C, of light yellow color, and of low viscosity is obtained which is then poured into molds, then demolded to obtain suppositories which are stored in the refrigerator.

It goes without saying that the dosage of active ingredients depends on the active ingredient administered.

The microemulsions obtained melt or dissolve frankly in a temperature range between 34 and 37 ° C., which makes it possible to give the active principles, in particular lipophilic agents, excellent bio-availability, with possibly a prolonged release by a reservoir effect. . Example 1:

As the lipophilic phase, a solid mixture of hemi-synthetic glycerides is used, consisting of a mixture of mono-, di- and triglycerides of saturated Cs -Ci 8 fatty acids, marketed by the Applicant under the registered trademark "SUPPOCIRE DM ". This mixture, richer in tri- than in di- and endi- than in monoglycerides, is in the form of a waxy solid having a drop point (Mettler) between 42 and 45 ° C, sparingly soluble in ethanol and insoluble in water.

As surfactants (TA), saturated polyglycolysed Cs-Cio glycerides are used, marketed by the Applicant under the trademark "LABRASOL", consisting of a Cs-Cio coester of glycerol and polyethylene glycol of average molecular weight 400, which is in the form of an oily liquid having a lipophilic hydrophilic balance of 14, very soluble in ethanol and soluble in water.

As cosurfactant (CoTA), a polyglycerol oleate marketed by the Applicant under the registered trademark "LAUROGLYCOL", consisting of a 2-methyl-hepta-decanaate of polyglycerol, having a hydrophilic-lipophilic balance (HLB) of 10, is used. in the form of a viscous liquid, soluble in ethanol and dispersible in water.

In all of the examples below, the ratio between the surfactant and the co-surfactant is 1, and the proportions between the lipophilic phase and the TA / CoTA mixture are varied. The results are collated in Table I. To determine the zones of existence of a microemulsion, pseudo-ternary diagrams are drawn while preserving a TA / co-surfactant CoTA) ratio of 1. Lipohile phase mixtures (TA / CoTA) are produced in different proportions.

To each of these mixtures, water (or the hydrophilic phase) is added dropwise, until a clear solution is obtained. The amount added corresponds to the minimum percentage in hydrophilic phase necessary to enter the microemulsified zone. It is the percentage of entry. If we continue to add the hydrophilic phase, in particular water drop by drop, we then witness the appearance of a cloudiness. The quantity added corresponds to the exit percentage.

The method used is called the "titration method". It is the transparency which spontaneously and brutally succeeds the milky appearance of an emulsion, which serves as a criterion for fixing the limits of the domains of existence of the microemulsions.

On the diagram given in FIG. 1, corresponding to Example 1, it can be seen that the zone in which a microemulsion is obtained, corresponds to a percentage of water of between 1.16 to 2.25%, while the rest of the form consists of a TA / CoTA mixture at 60% (sixty percent) and 40% (forty percent) for a lipophilic phase. o

Zero indicates an infinitely small amount of water

Example 2:

A pre-microemulsion forming in situ is prepared using 70% (seventy percent) of a mixture of triglycerides marketed by the Applicant under the brand "SUPPOCIRE CM" and 15% (fifteen percent) of a surfactant -active agent marketed by the Applicant under the name "TRANSCUTOL" at the rate of:

- 15% (fifteen percent) of diethylene glycol monoethyl ether;

- 15% (fifteen percent) of a co-surfactant based on lauroglycol.

Example 3:

Example 2 is repeated, replacing the mixture of glycerides

"SUPPOCIRE CM" by another mixture sold under the brand

"SUPPOCIRE CS2X" at a rate of 65.6%, the proportion of transcutol is brought to 16.7%, that of LAUROGLYCOL also to 16.7% and 1% (one percent) of water is added.

E em 4:

Example 3 is repeated, removing the water and retaining the same proportion of compounds as in Example 2.

Example 5:

Example 2 is repeated with the following quantities: SUPPIRE CM: 59% TRANSCUTOL: 13%

Cotensioactif PLUROL OLEIQUE: 13% IBUPROFENE (DO: 15%. Example 6:

As lipophilic phase, a solid mixture of hemi-synthetic glycerides sold by the Applicant under the registered trademark "SUPPOCIRE BM", richer in triglycerides than that of Example 1 and having a drop point of between 35 and 37 °, is used. vs.

By operating as in Example 1, five percent (5%) of an anti-inflammatory active ingredient (indomethacin) is added to this phase.

The diffusion of the active principle of this conventional suppository formulation is measured through a cellophane membrane by the MURANISHI method on a TOYAMA SANGYO model TMS-103 device in a buffer solution at pH 7.2. The results are collated in Table II below.

Example 7:

By operating as in Example 1, a suppository in accordance with the invention is prepared, containing in percent: lipophilic phase (as in Example 6):

SUPPIRE BM) 57%

. surfactant (TRANSCUTOL of Example 2) 19%

. cosurfactant (PLUROL OLEIQUE from Example 2) 19%. active ingredient: indomethacin from Example 6 5%.

The hydrophilic phase is provided by the rectal fluid. TABLE II

Time in Percent of active ingredient broadcast minutes

Example 7 (invention) Example 6 (prior art)

0.11 0.48 0.96 1.38 1.85 2.37 2.89 3.41 3.88 4.35 4.77 5.20

5.67

Diffusion is measured under the same conditions as in Example 6 and the results are collated in Table U.

It is therefore found that a suppository according to the invention (example 7) diffuses almost twice as fast as a conventional suppository (example 6), which suggests better bioavailability. The excipients according to the invention have many advantages compared to those marketed to date. We can cite :

- Excellent power to dissolve the active ingredient, particularly if it is lipophilic; - good bioavailability since the characteristic microemulsion dissolves frankly in the human body, while thus avoiding the effect of first hepatic passage, which gives the drug a better efficacy;

- a prolonged release by reservoir effect due to storage of the active ingredient in the epithelium of the rectal mucosa.

These excipients can therefore be used successfully for the manufacture of suppositories.

Claims

1 / Excipient for a pharmaceutical suppository, consisting of a microemulsion comprising in mixture:. at least one hydrophilic liquid phase, chosen from the group comprising water, alcohols, polyols, glycerol, alone or as a mixture; . at least one lipophilic phase consisting of a mixture of glycerides; . at least one short chain surfactant based on polyethylene glycol; . at least one co-surfactant based on polyglycerol, characterized:

- in that the lipophilic phase is solid and represents from 30 to 70% (thirty to seventy percent) of the weight of the microemulsion;

- in that the hydrophilic phase represents at most 5% (five percent) by weight of the microemulsion;

- And in that the mixture of surfactant and cosurfactant represents from 30 to 50% (thirty to fifty percent) of the weight of the microemulsion.

2 / excipient according to claim 1, characterized in that the hydrophilic liquid phase is water in an amount of 0.5% of the weight of the microemulsion.

3 / excipient according to claim 2, characterized in that the water of the hydrophilic phase is supplied in situ by the rectal liquid. 4 / excipient according to claim 1, characterized in that the lipophilic phase consists of a mixture of mono, di and saturated triglycerides, richer in triglycerides than in diglycerides, and richer in diglycerides than in monoglycerides.

5 / excipient according to claim 4, characterized in that the mono, di and triglycerides are hemi-synthetic glycerides of saturated fatty acids Cs to Ci8.

6 / excipient according to claim 5, characterized in that the glycerides are associated with polyoxyethylenated fatty esters.

7 / excipient according to claim 1, characterized in that the lipophilic phase consists of saturated polyglycolized glycerides.

8 / excipient according to claim 1, characterized in that the lipophilic phase represents from 50 to 55% (fifty to fifty five percent) of the weight of the microemulsion.

9 / excipient according to claims 1, characterized in that the surfactant is a Cs-Cio coester of polyethylene glycol glycerol of molecular weight close to 400, and in that the cosurfactant is an ester d '' a liquid fatty acid of oleic or isostearic acid and a polyol of molecular weight between 100 and 1000. 10 / A method for preparing a pharmaceutical suppository from an excipient consisting of a microemulsion according to one of claims 1 to 9, characterized in that it consists:

- firstly, heat until the solid lipophilic phase liquefies; - Then, to maintain this mixture in fusion while reducing its temperature between 30 and 35 ° C;

- Then, with gentle stirring, and always at a temperature between 30 and 35 ° C, to add the mixture of surfactants, cosurfactants and active ingredients; - then, to add to this molten mixture at most 5% (five percent) by weight of water;

- And finally, to homogenize the mixture obtained, then to pour it in the form of suppositories, which is removed from the mold after cooling.