MXPA00010497A - Pharmaceutical compositions capable of being gelled - Google Patents

Abstract

The invention concerns fluid pharmaceutical compositions for controlled release of at least one active substance comprising:a) a therapeutically efficient amount of at least one active substance;b) 3 to 55 wt.%of phospholipid;c) 16 to 72 wt.%of one or several pharmaceutically acceptable solvents;and d) 4 to 52 wt.%of at least one fatty acid. Said composition is characterised in that it has the property of being instantaneously gelled in the presence of an aqueous phase. The invention also concerns methods for preparing said compositions and their use for treating a human being or animal.

Description

GELIFICABLE PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions that allow the prolonged release of at least one active substance, to methods of preparing these compositions, as well as to their use for the administration of medicaments subcutaneously and / or intramuscularly.

BACKGROUND OF THE INVENTION The two main ex tra vessels are parenteral administration routes are subcutaneous and intramuscular. With respect to intravenous injection, these two administration routes for the same aqueous solution of active principle generally produce a slightly different and slightly prolonged effect. The bioavailability of the drug is thus generally lower due to absorption Ref. 124257 slower, fixation or degradation of the drug at the injection site or in the crossed tissues. Thus the TRH (thyrotropin that releases the hormone, a tripeptide) to a bioavailability in the mouse of 67.5% after subcutaneous administration and 31.4% after intramuscular administration (Redding TW and Schally AV, Life Sci., 12. 23 (1970)). To improve bioavailability and obtain true prolonged-release preparations, different experimental forms have been developed. Thus, encapsulation by liposomes of P-18, a peptide of molecular weight less than 5000 Daltons, shows that after intramuscular injection, the peptide remains 7 days at the injection site level (Crommelin DJA and Storm G., Int. Pharm. J., 1, 179 (1987)). Another means that prolongs the release of an active ingredient consists of its incorporation into an implant. These implants can be prepared from biodegradable polymers or not. The disadvantage of this form is linked to its mode of subcutaneous introduction by incision or with the help of a trocar. In addition, if a non-biodegradable polymer is used, the implant should be removed by incision after the diffusion of the entire active ingredient out of the polymer matrix. These systems have been extensively developed for the administration of hormones such as LHRH (luteinizing hormone releasing hormone) and its synthetic analogues. Thus, gosereline administered in man in the form of PLA-GA implants (copolymer of lactic acid and glycolic acid) allows a very important and durable decrease of testosterone levels in the blood (Vogelzang NJ, Chodak GW, Soloway MS , Block NL, Schellhammer PF, Smith JA, Caplan RJ and Kennealey GT, Urology, 46, 220 (1995)). Other polymeric supports can also be used, micro or nanoparticles. In this case, only biodegradable polymers are used. With regard to the implants, these particles can be injected with the help of a conventional syringe but present the inconvinient of not being able to be removed from the organism in case of problem. A very important and durable decrease in testosterone levels have also been observed in man after the administration of PLA-GA microparticles containing nafareline. These different administration systems have the disadvantage of a sophisticated and complex preparation which demands the particular facilities. The Applicant has now discovered new pharmaceutical compositions, obtained by an extremely simple preparation procedure and which allows a prolonged release of an active principle. These compositions have the property of instantly gelling in the presence of an aqueous phase. They can be judiciously used to obtain, through the subcutaneous and intramuscular routes, a sustained and scheduled release of medications. At the contact of the mucous membranes, a gel will form under the skin or in the muscle and the drug can diffuse and be released from the gel. Lipid compositions which undergo a phase transformation upon contact with water have already been reported in the literature.

The European patent application 550960 describes the compositions for topical application, intended to prevent perspiration, comprising an agent that prevents transpiration, which comprises at least one amphiphilic substance, this agent prevents transpiration that is capable of forming a phase liquid crystalline insoluble in water, having a periodicity greater than 1. In particular, Example 14 illustrates a composition capable of forming an inverse hexagonal crystalline phase at the contact of perspiration, composed of 34 to 50% oleic acid and 50 to 66% lecithin (phosphatidylcholine). The international patent application WO 94/10978 describes emulsifying compositions intended to replace synthetic emulsifiers commonly used in the food, cosmetic, repair or pharmaceutical industry. These compositions comprise at least one membrane lipid (phospholipid), at least one natural amphiphile which is not a primary emulsifier (fatty acid or fatty alcohol in C12 to C22, or combination of a fatty acid and a fatty alcohol), and, optionally, a hydrophilic medium (aliphatic alcohol such as propylene glycol). These compositions possess the property of forming creams (emulsion of oil in water) with oils or oily substances and are capable of forming stable emulsions or creams when they are mixed with liposomes. More particularly, Example 4 describes a composition consisting of 15% by weight of hydrogenated soy lecithin (phospholipid), 15% by weight of fatty acid, 45% by weight of fatty alcohol and 25% by weight of alcohol (10% ethanol and 15% glycerol). This composition is presented in the form of a wax (soft wax mass). The literature also mentions fluid pharmaceutical compositions intended for the treatment of adon t i t i s, which are presented in the form of more or less viscous suspensions or emulsions which are administered in the periodontal pocket, generally with the help of j eringas. The international patent application WO 95/34287 discloses biodegradable lipid compositions in the form of crystalline phases L2, which allow controlled release of active substances and which comprise, in addition to the active substance, at least one diacylglycerol of unsaturated fatty acid having 16 to 22 carbon atoms or of saturated fatty acid having from 14 to 22 carbon atoms, and at least one phospholipid chosen from the glycerol fatates and is fatphase phytophas, and optionally, at least one polar liquid chosen from water, glycerol, ethylene glycol and propylene glycol. These compositions have the particularity of being transformed into the contact of water in cubic liquid crystalline phases, which allows to "grind" the active substance in the place from where the action is desired to take place.This document mentions, among other applications, the possibility of using such compositions for the treatment of parodon titis However, the efficacy of such compositions in the treatment of periodontitis is not illustrated in this document European patent 429224 describes the compositions which are presented in the form of gels which they contain from 1 to 99% by weight of monoolein and from 1 to 90% by weight of active substance, which is located in the periodontal cavity.

In the presence of ambient water, these compositions are more viscous and keep the active substance close to their site of action. The active substance is slowly released in a controlled manner. Patent US 5230895 describes the use of compositions that are presented in the form of solutions or pastes capable of being transformed into gel when they are placed in the periodontal bag. These compositions are biodegradable and allow controlled release of the active substance at the site of action. They contain a mixture of glycerides and an active substance chosen in such a way that they are capable of forming a gel in the environment of the periodontal pocket. The compositions illustrated in this document contain at least 70% of Myverol ™ 18-92 which is a composition of litmus monoglycerides having an amount in monoglyceride of at least 90%. The patent US 5143934 describes the compositions that allow the administration by controlled release of an active substance in a periodontal bag, which comprises at least one monoglyceride and at least one vegetable oil in sufficient proportions to form a liquid crystalline phase upon contact of the water present in the periodontal bag. These compositions are solid at room temperature, but they have a melting point lower than body temperature.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to fluid pharmaceutical compositions that allow controlled release of at least one active substance comprising a) a therapeutically effective amount of at least one active substance, b) from 3 to 55% by weight of phospholipid, c) of 16 to 72% by weight of pharmaceutically acceptable solvent, and d) from 4 to 52% by weight of fatty acid, these compositions have the property of instantly gelling in the presence of an aqueous phase.

According to one aspect, the invention relates to processes for the preparation of these compositions. According to a third aspect, the invention relates to the use of these compositions for the controlled release of one or more active substances by subcutaneous and / or inmuscular injection. The compositions according to the present invention comprise a therapeutically effective amount of at least one active substance. The latter can be fat-soluble or water-soluble. Antibiotics, in particular antibiotics active against anaerobic bacteria, such as doxycycline or minocycline and their pharmaceutically acceptable salts, infectious agents, such as meth ronidazole, chlorhexidine, benzalkonium chloride, p-chlor omcres ol, 1,2-dichloro-1,2-dichloride alcohol, hexamidine or chlorophene and their pharmaceutically acceptable salts, local anesthetics such as lidocaine, procaine, tetracaine, articaine, bupivacaine, mepivacaine or prilocaine and its pharmaceutically acceptable, anti-inflammatory salts is teroid or other, such as hydrocortisone, cortisone, prednisone, predni-solone, methylpredni-solone, triamcinolone, betamethasone or dexamethasone and their pharmaceutically salts acceptable as well as aceclofenac, diclofenac, ibuprofen and piroxicam and their pharmaceutically acceptable salts, cosmic antimicrobials such as griseofulvin, amphotericin B, natamycin, nystatin and their pharmaceutically acceptable salts or also peptide active substances such as calcitonin, somatostatin, insulin, bone growth hormone and other growth factors or repair. The compositions according to the present invention contain from 3 to 55% phospholipid. The phospholipids which can be used according to the present invention are phosphoric esters of polyols and fatty acids. They can come from very varied sources, as natural as by way of synthesis. Phospholipids can be hydrogenated or non-hydrogenated. Examples of examples are phosphatidylcholine, hydrogenated phosphatidylcholine, salts of phosphatidylglycerol, dicaproylphosphotyldicholine or the salts of t-dayo-1-phosphatidylglycerol. These phospholipids can also be used in mixture. Preferably, the phospholipid present in the compositions according to the present invention is phosphatidylcholine. When the phospholipid is chosen from phosphatidylcholine, salts of phosphatidylglycerol, dicaproylphosphotidylcholine or salts of dies tearoyl fos fat idylglycerol, the preferred compositions according to the present invention contain from 15 to 55% by weight of phospholipid. When the phospholipid is a hydrogenated phosphatidylcholine, the compositions according to the present invention contain from 3 to 11%, preferably from 3 to 10% by weight of phosphatidyl phospholipid. The compositions according to the present invention contain one or more pharmaceutically acceptable solvents. By pharmaceutically acceptable solvent is meant a solvent such as propylene glycol, polyethylene glycols, mineral oils such as paraffin oil or silicone oils or any other solvent in which the phospholide used is soluble. Mixtures of various pharmaceutically acceptable solvents can also be used. Propylene glycol is preferably used. The solvent used is pharmaceutically acceptable, which means that the solvent will not produce biological reaction that is translated by infections, inflammations or other phenomena of rejection. The compositions according to the present invention also contain from 4 to 52% of at least one fatty acid. The fatty acids which can be used according to the present invention are saturated or unsaturated organic carboxylic acids containing from 4 to 22 carbon atoms, preferably from 8 to 18 carbon atoms. By way of example, oleic acid, caprylic acid, capric acid, caproic acid, myristic acid, butyric acid, etc. can also be used. Mixtures of fatty acids can also be used. The preferred fatty acid according to the present invention is oleic acid. Optionally, the compositions according to the present invention can also contain up to 15% by weight of water. It will be noted that the amount of water present in the compositions according to the invention is chosen so that the composition has the desired consistency for the intended application. The applicant has also discovered that phospholipids which occur in the form of commercial mixtures are suitable for the compositions according to the present invention. As an example of such commercial compositions, mention should be made of Phosal 50 PG ™ (55.8% phosphatidylcholine, 1.9% soybean fatty acids, 2.9% litmus monoglycerides, 1.9% ethanol, 37.3% propylene glycol, 0.2% ascorbyl palmitate). ), Phosal 53 MCT ™ (60.8% phosphatidylcholine, 2% oleic acid, 3% litmus monoglycerides, 5% ethanol, 29% triglycerides, 0.2% ascorbyl palmitate), available from NATTERMANN PHOSPHOLIPID GmbH. The compositions according to the present invention may also contain the following optional components: up to 5% by weight of monoglyceride or diglyceride or of a mixture of mono- and diglyceride and / or up to 15% by weight of triglycerides. The compositions according to the present invention may further contain one or more preservatives (such as ethanol), one or more antioxidant agents (such as ascorbyl palmitate) or one or more complexing agents (such as EDTA (ethylenediamine). you t raace tato)). The compositions according to the present invention allow the controlled ase of at least one active substance. By controlled ase, it is understood a profile of ase of the active substance desirable for the contemplated treatment. The ase of the active substance can be more or less retained or decreased depending on the active substance used and the therapeutic effect sought. It will be noted that the control of the ase of the active substance can easily be obtained by simple variations of proportions of components of the compositions according to the present invention. They lend themselves very well to various therapeutic applications in which the controlled ase of an active substance in a well-defined biological site is sought. The compositions according to the present invention are fluid pharmaceutical compositions which are presented in the form of emulsions, suspensions or oily preparations. They possess the property of instantly gelling in the presence of an aqueous phase. In fact, when the compositions according to the present invention are placed in the presence of an excess of aqueous phase, they pass from a fluid state to a gel state immiscible with the aqueous phase nearby. According to another aspect, the present invention tes to methods of preparing the compositions according to the present invention. The compositions according to the present invention are obtained by a process comprising the following successive steps: i) the phospholipid (s) are dissolved in the pharmaceutically acceptable solvent (s); ii) the fatty acid (s) are added to the phospholipid solution under agitation; iii) the active substance or substances are incorporated into the mixture obtained at the end of stage ii), and iv) the water is optionally added to the composition obtained in stage iii). When the active substance is water-soluble, it dissolves in a minimum amount of water before the incorporation of step iii). When the active substance is not soluble in water, it is incorporated in step iii) into the mixture of phospholipid, pharmaceutically acceptable solvent and fatty acid. In the case of a substance that is both water-insoluble and with little or no fat-soluble material, it is also incorporated into step iii), possibly under the micronized form. The following examples illustrate the present invention without, however, limiting it. In these examples, all parts are expressed by weight. The following commercial products were obtained from NATTERMANN PHOSPHOLIPID GmbH and have the following compositions (percentages by weight): Phospholipon 90 ™: phosphatidylcholine; - Phosal 50 PG ™: 55.8% phosphatidylcholine, 1.9% soybean fatty acids, 2.9% litmus monoglycerides, 1.9% ethanol, 37.3% propylene glycol, 0.2% ascorbyl palmitate; - NAT 8449 ™: 60% phosphatidylcholine, 40% propylene glycol: - Phosal 53 MCT ™: 60.89% phosphatidylcholine, 2% oleic acid, 3% litmus monoglycerides, 5% ethanol, 29% triglycerides, 0.2 % ascorbyl palmitate; Phospholipon G-Na ™: sodium salt of 3 (3 -sn-fos fat idyl) soy glycerol; Phospholipon CC ™: 1, 2 -dicapr oi 1-sn-glycero (3) phosphocholine; Phospholipon SG-Na ™: sodium salt of 1,2-distearoyl-sn-glycerol (3) phospholglycerol; - Phospholipon 90 H ™: (3-sn-phosphat idyl) hydrogenated soybean hill.

Example 1.

This example illustrates the preparation of various compositions according to the invention. The compositions described above are presented in the form of more or less viscous emulsions, suspensions or solutions which instantly gel in the presence of an aqueous phase.

General operating mode a Phosal 50 PG ™ or NAT 8449 ™ and oleic acid are mixed under agitation. The active substance is introduced into the mixture under agitation. After homogenization, the water is optionally added to make the preparation more viscous.

General operating mode b: Phosal 50 PG ™ or NAT 8449 ™ and oleic acid are mixed under agitation. The active substance dissolves in the water, and the solution thus obtained is introduced into the mixture Phosal 50 PGTM or NAT 8449TM oleic acid under agitation 1. 1 Preparation of met ronidazole benzoate.

The preparations having the compositions presented in Table 1 are obtained following the general operating mode a.

Table C omp o s i c i one s A B Metronidazole (parts) Composition Ai A2 A3 Bi B2 Phosal 50 PG ™ 54.6 77.4 81.9 NAT 8449 ™ 72.8 45.5 oleic acid 36.4 13.6 9.1 18.2 45.5 etrodinazole benzoate 5.0 5.0 5.0 5.0 5.0 water 4.0 4.0 4.0 4.0 4.0 4.0 1. 2 Preparation of chlorhexidine diacetate The preparations having the compositions presented in Table 2 are obtained following the general operating mode a.

Table C omp ositions D chlorhexidine (parts) Composition Ci C2 Di D2 Phosal 50 PG ™ 51.0 63.8 NAT 8449 ™ 59.5 51.0 Oleic acid 34.0 21.2 25.5 34.0 Chlorhexidine diacetate 15.0 15.0 15.0 15.0 1. 3 Preparation of doxycycline hyclate The preparations having the compositions presented in Table 3 are obtained following the general operating mode b.

Table Compositions Doxycycline (parts) Composition Ei E2 Fi F2 Phosal 50 PG ™ 43.0 64.5 - - NAT 8449 ™ - - 51.6 34.4 oleic acid 43.0 21.5 34.4 51.6 doxixicinium hyclate 5.0 5.0 5.0 5.0 water 9.0 9.0 9.0 9.0 1.4. Preparation of Minocycline Hydrochloride Preparations having the compositions presented in Table 4 are obtained following general operating mode a.

Composition Table H Mino ci c l in a (p a r t e s) Composition Gi G2 Hi H2 Phosal 50 PG ™ 45.5 77.4 - - NAT 8449 ™ - - 68.3 45.5 oleic acid 45.5 13.6 22.7 45.5 Minocycline hydrochloride 5.0 5.0 5.0 5.0 water 4.0 4.0 4.0 4.0 1. 5. Preparation of 1,2-dichlorobenzyl alcohol The preparations having the compositions presented in Table 5 are obtained following the general procedure a.

Table 5 - Compositions I and J 1,2-Dichlorobenzyl alcohol (parts) Composition Phosal 50 PG ™ 8 0 NAT 8 4 4 9 ™ 80 Oleic acid 19 19 1,2-dichlorobenzyl alcohol 1. 6. Preparation of hydrocortisone succinate The preparations having the compositions presented in Table 6 are obtained following the general procedure b.

Table Comp i ossions K Hydrocortisone (parts Composition K Phosal 50 PG ™ 80 NAT 8449 ™ 67.0 oleic acid 15 28.0 hydrocortisone water succinate 1. 7. Preparation of lidocaine hydrochloride The preparations having the compositions presented in Table 7 are obtained following the general procedure b.

Table 7 - Compositions M and N - Lidocaine (parts) Composition M N Phosal 50 PG ™ 80 NAT 8449 ™ 66 oleic acid 14 28 hydrochloride of -i lidocaine X water 1. 8. Preparation of the somatos tat ina The preparations having the compositions presented in Table 8 are obtained by following the following operating modes: preparation Zi: operating mode a; preparations Z2 to Z5: operating mode b.

Table 8 Compositions Zi Z5 Somatos tat ina (parts) Composition Zi Z2 Z3 Z4 Z5 Phosal 50 PG ™ 85 62.25 74.70 62.25 74.70 NAT 8449 ™ - 8.30 - 8.30 Propylene glycol 20.75 - 20.75 - oleic acid 14.95 13 13 13 13 Somato s tat ina 0.05 0.05 0.05 0.05 0.05 Acetic Shock Absorber 3.95 3.95 - - Acoustic Shock Absorber + 7.5% Na Lauryl Sulfate _ _ _ 3.95 3.95 Example 2. Release tests 2. 1. Preparations A2 and Bi prepared in Example 1 were subjected to a release test carried out in accordance with the standards of the 23rd edition of the U.S. Pharmacopoeia. (USP 23), which uses the apparatus n ° l at a temperature of 37 ° C, the vanes are rotated at 50 rpm. This test has shown that the A2 preparation released approximately 60% of the active principle in 6 hours, the release proceeds slowly to achieve approximately 65% in 24 hours. When in the preparation Bi, it releases approximately 45% of the active principle in 6 hours, then the release continues slowly to reach approximately 55% in 24 hours. 2. 2 The preparations Zi to Zs prepared in example 1 have been subjected to a release test carried out in accordance with the standards of the 23rd edition of the U.S. Pharmacopoeia. (USP 23), which use the apparatus n ° l at a temperature of 37 ° C, the blades rotate at 50 rpm. This test has shown that the Zs preparation releases approximately 23% of the active ingredient in 24 hours, the release was continued to reach approximately 31% in 48 hours; the Z3 preparation releases approximately 18% of the active principle in 24 hours; the Zi preparation releases approximately 14% of the active principle in 24 hours; the preparations Z2 and Z4 release approximately 7% of the active principle in 24 hours. These results show that it is possible to influence the release of the active principle by modifying the composition of the preparations.

Example 3 This example shows that different pharmaceutically acceptable solvents can be used in the compositions according to the present invention. 3. 1. Composition O: Phospholipon 90 ™ (30 parts by weight) are hot dissolved in polyethylene glycol 400 (45 parts by weight). After cooling, the oleic acid is added under stirring. Upon contact of an aqueous solution, the preparation gels instantaneously. This example shows that propylene glycol can be replaced by PEG 400. 3. 2. Compositions P: 40.9 parts of NAT 8449 ™, 27.3 parts of PEG 400, 22.8 parts by weight of oleic acid are mixed under stirring. Water (9 parts by weight) is added under stirring to make the preparation more viscous.

The preparations having the compositions presented in Table 9 are obtained by following this procedure.

Table 9 - Compositions P (parts) Compositions Pi P2 Pa NAT 8449 ™ 34.1 40.9 61.4 PEG '400 34.1 27.3 6.8 oleic acid 22.8 22.8 22.8 water 9.0 9.0 9.0 Example 4 This example shows that the compositions according to the present invention may also contain the triglycerides. Composition Q: 61.2 parts of Phosal 50 PG ™, 20.4 parts of Phosal 53 MCT ™ and 14.4 parts of oleic acid are mixed under stirring. 4 parts of water are then added to this mixture under stirring. This preparation gels insensitively upon contact of an aqueous phase.

Example 5 This example shows that the compositions according to the present invention can contain different types of phospholipids. The phospholipids used are the sodium salt of 3-. { 3-sn-fos fatidil) soy glycerol. { Phospholipon G-Na ™), 1,2 -dicaproyl-sn-glycero (3) phosphocholine (Phospholipon CC ™), the sodium salt of 1,2-distearoyl-sn-glycero (3) phosphoglycerol (Phospholipon SG-Na ™ ) and hydrogenated soybean (3-sn-phosphat-1) hydrogenated soybean hill (Phospholipon 90H ™) The compositions P presented in Table 10 are obtained by mixing the various components under agitation. These four compositions instantly gel in the presence of an aqueous phase.

Table 10 - Compositions R (parts) Composition Ri R2 R3 R4 Phospholipon G-Na TM ~ 30 - Phospholipon CC TM 30 Phospholipon SG-Na ™ 15 Phospholipon 90H M 3 PEG 400 45 45 60 72 Oleic acid 25 25 25 Example 6 This example shows that the oleic acid can be replaced by other fatty acids or by a fatty alcohol in the compositions according to the present invention. The compositions S presented in Table 11 are obtained by mixing the various components under stirring. These four compositions instantly gel in the presence of an aqueous phase.

Table 11 - Compositions S (parts) Co-position Si S2 S3 S4 Phosal 50PG ™ 80 80 80 80 caprylic acid 20 capric acid 20 oleic acid 20 Oleic alcohol 20 Example 7. Measurement of the release rate as a function of the excipients. 7. 1. The compositions T presented in Table 12 are obtained by adding the required amount of a 10% aqueous solution of Sicomet-FDC blue dye 1 to the mixture of other components under stirring. The compositions Ti a Te are instantly gelled in the presence of an aqueous phase; the gel is more fluid for the composition T ?.

Table 12 - Compositions T (parts) Control composition Ti t2 t3 T4 t5 e t7 Phosal 50PG ™ - 81.6 68.3 68.3 68.3 68.3 68.3 40.8 Oleic acid - 14.4 22.7 18.2 13.7 18.2 9.0 14.4 Miglyol 810N ™ - - - 4.5 9.0 - 13.7 - Phosal 53 MCT ™ - - - - - 4.5 - 40.8 Solution of? Oa 4.0 9.0 9.0 9.0 9.0 9.0 4.0 coloring The release test is carried out as follows. Equal amounts of the Ti to T7 preparations and of the control solution are deposited in a deep well at the center of a constant thickness layer of trypticase soy agar cast in a Petri dish. The diffusion rate of the dye is determined by measuring the diameter of the dye stain as a function of time. The results obtained for the control solution and the solutions Ti to T7 are recovered in Table 13.

Table 13 - Release rate of the preparations Ti to T7.

Time Diameter of the spot in m. (hours) Control T2 Tj T5 T6, T7 0 16.97 18.74 18.61 17.66 18.36 18.49 3 49.55 - - - - - 6 62.18 29.56 29.14 28.58 23.12 33.33 24 90.10 51.00 30.38 30.57 24.59 52.96 36 96.29 57.45 34.02 33.67 31.23 54.55 72 108.52 60.45 39.29 34.58 31.82 68.67 No diffusion is observed This example shows that the release rate of an active substance can be controlled by the choice of components of the preparation. 7. 2. Analogously, compositions U taken in Table 14 have been prepared.

Table 14 - Compositions U (parts) Composition Ui U2 U3 U4 Phosal 50PG ™ 72.0 81.6 86.4 91.2 Oleic acid 24.0 14.4 9.6 4.8 Dye solution 4.0 4.0 4.0 4.0 A release test as described in Example 7.1 is carried out on the compositions Ul to U4: by comparison, a release test is carried out simultaneously with the T7 solution and with a 10% solution of Sicomet-FDC blue 1 (control ). The results of this test are presented in Table 15.

Table 15 - Release rate of the preparations Ui to U4 and T7. Time Diameter of the stain in mm. (hours) control Ui U2 U3 U4 U7 2 46 18 24 27 24 18 -4 55 18 28 34 26 18 6 62 18 33 40 28 18 24 82 23 48 47 37 18 These results show that the release rate of an active substance can be controlled by the choice of components of the preparation.

Example 8. Live assay. Subcutaneous and intramuscular injection of a preparation with calcitonin. Calcitonin causes a decrease in the serum calcium level in direct relation to its activity. During these tests, the evolution during the time of serum calcium rate in the rat was followed after the subcutaneous or intramuscular injection of preparations according to the invention containing 20 IU of salmon calcitonin. 8. 1. Formulations.

The compositions comprising the salmon calcitonin used in these tests are recorded in Table 16.

Table 16 - Compositions X (parts) Composition Xi X2 X3 Phosal 50PG TM 40.8 81.6 Phosal 53 MCT, TM 40.8 oleic acid 14.4 14.4 calcitonin 10000 Ul 10000 Ul 10000 Ul acetic buffer pH 4.3 100 4.0 4.0 The calcitonin used contains 5660 IU / mg. The 10000 Ul present in the preparations Xi to X3 corresponds to 1,767 mg. 8. 2. Animal experimentation The experimentation was carried out in two groups of 18 Wistar male rats conscious and without fasting (provenance IFFA CREDO) weighing 169.1 g to 193.6 g (average: 183.0 g: type of deviation: 5.9 g), for the first group, and a weight of 170.2 g to 189.1 g (average: 180.0 g, type of deviation: 5.2 g), for the second group. Each group of 18 animals are divided into 3 series of 6: First group: • series 1: each rat collects subcutaneously in the abdominal region 200 μl of preparation Xi, or 20 ul of calcitonin; • series 2: each rat collects subcutaneously in the abdominal region 200 μl of preparation X2, or 20 ul of calcitonin; • series 3: each rat collects subcutaneously in the abdominal region 200 μl of preparation X2, or 20 ul of calcitonin. Second group: • series 4: each rat picks up intramuscularly in the muscle of the thigh 200 μl of preparation Xi, or 20 IU of calcitonin; • series 5: each rat picks up intramuscularly in the muscle of the thigh 200 μl of the preparation X2 / or 20 IU of calcitonin; • series 6: each rat picks up intramuscularly in the muscle of the thigh 200 μl of preparation X2, or 20 ul of calcitonin.

After the administration of the preparations, the rats recover a feed poor in calcium and deionized water. Blood samples of 300 μL are taken at the level of a caudal vein before administration (t = 0) and the following time after administration: 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 32 h and 48 h. The samples rest 1 h at room temperature before undergoing 2 successive centrifugations at 6,000 rpm for 10 minutes. The recovered sera are frozen at -20 ° C until the serum calcium is dosed. 8. 3. Dosage of serum calcium A 90 μL serum sample is added to 2 mL of a lanthanum chloride solution (15 mmol / L) in hydrochloric acid (50 mmol / L). The calcitic rate of the sample thus diluted is measured with the help of a spectrophotometry of atomic absorption (Varian Spectra A-40) (Extinction at 422.7 nm). The contrast curve is made by eliminating 5 standard solutions: - a blank containing sodium chloride (140 mmol / L), potassium chloride (5 mmol / L), hydrochloric acid (30 mmol / L) and magnesium acetate (1 mmol / L) standard solutions containing more than the calcium carbonate target at concentrations of 1.25 / 2.5 / 5 and 7.5 mmol / L. The apparatus is contrasted before each series of rats. The calcic rate of the samples is calculated from the contrast curve (Data Station Variant). The calculated concentrations are expressed below as a percentage of the initial value, ie the value obtained before any treatment (t = 0). These initial values vary according to the animal from 3.34 to 2.26 mmol / L. The results obtained with series 1, 2 and 3 (subcutaneous administration) are presented in Table 17 which takes the means of the serum calcium rates expressed as a percentage of the initial concentration (t = 0) and the type errors on these means obtained by the preparations Xi, X2 and X3.

Table 17 - Calcium serum rates + _ type error as a function of time after subcutaneous injection of formulations Xi, X2 and X3.

Time (h) Xi X2 X3 0 100 100 100 0. 5 86.52 + _2.90 91.11 + 1.59 90.72 + _2.17 1 80.33 + _4.29 84.00 + _2.05 86.59 + _2.39 2 69.13 + 1.79 74.43 + 2.38 75.69 + _l .62 4 59.26 + _0.86 73.62 + _4.41 69.19 +2.39 8 55.04 + _l .12 82.30 + 7.26 66.52 + 1.13 24 97.14 + _2.38 95.65 + 3.93 73.38 + _3.59 32 101.03 + 2.99 93.85 + _3.90 75.98 + _2.40 48 97.32 + 3.44 100.09 + 1.75 87.13 + 1.51 The results obtained with series 4, 5 and 6 (intramuscular administration) are presented in Table 18 which takes the means of the serum calcium rates expressed as a percentage of the initial concentration (t = 0) and the type errors on these means obtained for the preparations Xi, X2 and X3.

Table 18 - Calcium serum rates + _ type error as a function of time after the intramuscular injection of formulations Xi, X2 and X3.

Time (h) Xi X2 X3 0 100 100 100 0. 5 86.51 + 2.09 89.06 + _l .39 88. 2 1 + 1 .64 2 78.77 + _l .80 79.31 + L .55 81.81 + .1.86 2 73.89 + _l .82 75.82 + _2.52 75.95 + 1.31 4 65.63 + l .32 68.58 +2.14 72.74 + 1.57 -8 62.93 + 1.55 63.91 + L .45 66.01 + 1.55 24 83.70 + _3.25 78.66 + _4.07 74.12 + _2.38 32 94.50 + 1.70 85.83 + _4.41 78.12 + _2. 24 48 98.53 + 2.76 105.33+ .15 100.62 + 1.34 These results show a prolongation of the effect of calcitonin, after subcutaneous or intramuscular administration, of several hours for preparations X2 and X3 in relation to the effect of reference solution Xi, this effect is more important for preparation X3 than for the X2 preparation.

These tests show that it is possible to modulate in vivo the biological activity of the active principle by modifying the composition of the preparations. This appears clearly in table 19, which takes the biodi sponibil ities. relative (in relation to solution Xi) of preparations X2 and X3 after subcutaneous (s.c.) and intramuscular (i.m.) injections Table 19 - Relative bioavailability (%) of preparations X2 and X3. Injection X2 X3 Subcutaneous 63.89 172.56 Intramuscular 110.41 128.72 It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (14)

1. Pharmaceutical composition in fluid form characterized in that it allows the controlled release of at least one active substance comprising a) a therapeutically effective amount of at least one active substance, b) from 3 to 55% by weight of phospholipid, c) from 16 to 72% by weight of pharmaceutically acceptable solvent, and d) from 4 to 52% by weight of the fatty acid, the composition has the property of gelling instantaneously in the presence of an aqueous phase.

2. The pharmaceutical composition according to claim 1, characterized in that the active substance is chosen from antibiotics, anti-infective agents, local anesthetics, anti-inflammatories, antimicroses or peptide active substances.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the phospholipid is chosen from phosphatidylcholine, salts of phosphatidylglycerol, dicaproylphosphatidylcholine and salts of distearoylphosphatidylglycerol, alone or as a mixture.

4. The pharmaceutical composition according to claim 3, characterized in that it contains from 15 to 55% by weight of phospholipid, preferably from 15 to 51% by weight of phospholipid.

5. The pharmaceutical composition according to claim 1 or 2, characterized in that the phospholipid is a hydrogenated phosphatidylcholine.

6. The composition according to claim 5, characterized in that it contains from 3 to 11%, preferably from 3 to 10% by weight of phospholipid.

7. The composition according to any of claims 1 to 6, characterized in that the pharmaceutically acceptable solvent is chosen from propylene glycol, polyethylene glycols or mineral oils such as paraffin oil or silicone oils, alone or as a mixture.

8. The composition according to any of claims 1 to 7, characterized in that the fatty acids used are saturated or unsaturated organic carboxylic acids containing from 4 to 22 carbon atoms, preferably from 8 to 18 carbon atoms.

9. The pharmaceutical composition according to claim 8, characterized in that the fatty acids are selected from oleic acid, caprylic acid, capric acid, caproic acid, myristic acid or butyric acid, alone or as a mixture.

10. The pharmaceutical composition according to any of claims 1 to 9, characterized in that it further comprises up to 5% by weight of monoglyceride or diglyceride or of a mixture of mono- and diglyceride and / or up to 15% by weight of triglycerides .

11. The method of manufacturing a pharmaceutical composition according to any one of claims 1 to 10, characterized in that it comprises the following successive steps: i) the phospholipid (s) are dissolved in the pharmaceutically acceptable solvent; ii) the fatty acid (s) are added to the phospholipid solution under agitation; iii) the active substance or substances are incorporated into the mixture obtained at the end of step ii), and iv) the water is optionally added to the composition obtained in step iii).

12. The process according to claim 11, characterized in that the active substance or substances are dissolved in a minimum amount of water before the incorporation of stage iii).

13. The process according to claim 11, characterized in that the active substance or substances are incorporated in step iii), possibly in the micronized form.

14. The use of a composition according to any one of claims 1 to 13 for the controlled release of one or more active substances by