EP2192894A2

EP2192894A2 - Novel method for producing dry hydrodispersible pharmaceutical forms

Info

Publication number: EP2192894A2
Application number: EP08827662A
Authority: EP
Inventors: Patrice Binay
Original assignee: Coretecholding
Current assignee: BIONETWORK
Priority date: 2007-07-06
Filing date: 2008-07-07
Publication date: 2010-06-09
Also published as: WO2009024686A2; RU2497502C2; FR2918277B1; US20130064897A1; CA2694059A1; FR2918277A1; JP5560188B2; WO2009024686A3; JP2010532336A; RU2010103999A; BRPI0814027A2; KR20100038188A

Abstract

The invention relates to life's necessities and in particular those relating to health, more particularly a method for dissolving and improving the intestinal absorption of active ingredients which are poorly-water-soluble or water-insoluble or which cannot be turned into salts in gastric juice, containing one or more active ingredients dispersed in a polyoxyethylene 32 fatty acid ester then hot spraying said dispersion onto a granular excipient in a fluid bed. The powder mixture thus formed is distributed in pharmaceutical compositions after optional dilution in a pharmaceutically-acceptable non-toxic inert excipient. The above is of use in the production of pharmaceutical compositions containing one or more pharmaceutically-acceptable non-toxic inert excipients.

Description

A novel process for producing water-soluble dry dosage forms and the pharmaceutical compositions thus obtained.

It has been known for many years that by the conventional exploration side of the pharmacological and toxicological properties of drugs, one of the determining factors of activity is the quantitative aspect of the resorption of the active component. Kinetics is becoming more and more the subject of systematic studies since the intensity of the response and often its nature is a function of the concentration obtained at the level of the receptor organ. The importance of these studies on pharmacokinetics, and consequently on bioavailability, has shown the interest of the modifications, especially galenical, made during the preparation of pharmaceutical forms, mainly in order to obtain the most appropriate ones for administration by the digestive tract.

The major problem of low intestinal resorption of drugs seems to be related to the fact that it occurs for a short time on a small area of the intestine. To increase this resorption, it is therefore important that the active ingredient is conveyed quickly and completely, in a form made soluble.

The drugs have low solubility in water or are poorly salifiable during passage into the stomach, so that they are only partially resorbed. Previous literature has indicated that digestive resorption can be favorably modified by the study of particle size, by the addition of nonionic surfactants in particular, as well as by the addition of a solubilizing agent.

Moreover, the micronization of the active ingredient adequately increases the external surface area of the powdery product and is already an approach to this problem. However, micronization is only appropriate for certain pharmaceutical forms, such as dispersions, or as a filler in capsules. It can not be a general solution for this problem of resorption because some active ingredients are difficult to micronize since too fusible or having a too fragile chemical structure.

The addition of surfactants can increase the solubility of certain active ingredients and thereby improve the resorption kinetics, but this does not systematically result in higher blood levels. In addition, it is often necessary to add significant amounts of surfactants (from 25 to 50%) to obtain a significant result. This improvement in the passage through the digestive tract seems to be the result of a decrease in surface tension involving an increase in the permeability of the digestive mucosa. Nevertheless, these large amounts of surfactants are often accompanied by a laxative effect that does not contribute to good absorption.

Another approach has been to add an emulsifier including a fatty acid ester of a carbohydrate (sucrose ester) and proceeds from another principle. This ester increases the lipophilicity of the molecule and thus facilitates the passage through the intestinal barrier. Nevertheless, this type of process gives conclusive results only with very lipophilic molecules and requires high concentrations of this ester.

More recently, to improve the absorption of active substances whose solubility in biological liquids is low, an attempt has been made to increase the kinetics of dissolution by producing solid dispersions. These solid dispersions, as defined by Chiou et al, in J. Pharm. Sci. 60 (194) 1281-1302, has been to realize a system which depending on the process, used for their production, may have different structures (see Fort and al., Pharm Acta HeIv 61 (3) (1986) 69- 88 or Bloc et al., Pharm Acta HeIv 62 (1987) 23-27) corresponding to different crystalline states. The vitreous state, although considered a solid state, has a liquid phase which contributes to its structural disorder. This vitreous state is not very orderly and easy to break. It contributes significantly to an increase in the dissolution rate, especially for substances that are poorly soluble in aqueous media. However, despite the large number of publications relating to the production of solid dispersions, especially based on Macrogols or Poloxamers, this technique has had limited development because of the difficulty in generalizing it. In some cases, the dissolution rate is large. In other cases, the dissolution rate is lower and tends to reach an asymptotic value.

Thus, for the same active ingredient and at similar concentrations, there were very significant variations in the dissolution rate depending on the nature of the co-melt agent. It has even been found, in some cases, the impossibility of obtaining a complete solubilization of the active ingredient, even after a prolonged contact time, or especially a tendency to recrystallization.

Another approach to this problem has been the production of solid dispersions of a therapeutic agent in a hydrophilic vehicle having increased solubility in the aqueous medium. This approach consists, first of all, in dissolving the therapeutic active ingredient in a very volatile organic solvent, in which a very hydrophilic polymer such as polyvinylpyrrolidone has been added. Then, the solvent is evaporated to dryness to form a co-precipitate of therapeutic agent and hydrophilic polymer.

This technique has made it possible to obtain a marked improvement in absorption kinetics, but it is not suitable for any type of active ingredient. In addition, this technique often requires the addition to the solution of a surfactant which increases the wetting ability by the digestive media and possibly limits the phenomenon of crystal formation occurring during the conservation of solid dispersions. The formation of crystalline products contributes to a decrease in the dissolution rate in time function (see Kigudin et al Chem Pharma Bull 9 (1961) 866-872, Duchene D. Pharma 1 (11) (1985) 1064-1073).

Moreover, this technique requires the formation of co-precipitates in a very hydrophilic lactam, such as polyvinylpyrrolidone, having a molecular weight ranging from 10,000 to 5,000, and an oxygenated or chlorinated solvent or mixtures thereof (see patent US-5776495).

A more recent approach is found in WO2005 / 034920 in the name of Life Cycle Pharma which describes the MeIt Dose technique. This technique allows better oral absorption of molecules with low solubility in water. This technique involves dissolving the molecules in a solvent that facilitates penetration into the epithelium of the intestinal tract to allow passage into the bloodstream.

The solvent described herein is a vehicle which can be hydrophobic or hydrophilic, which is miscible with water and has a melting point of less than 250 ° C. The preferred solvent is polyethylene glycol with or without Poloxamer 188.

Polyethylene stearate 32 is not mentioned in this document and the inert material necessary for the spraying of the vehicle is not micro-crystalline cellulose but lactose.

The present invention provides a much simpler and much more satisfactory solution to the problem of the dissolution and intestinal resorption of active ingredients with little or no water-soluble or non-salifiable in the gastric juice.

The process according to the invention consists in producing a dispersion of one or more active principle (s) in a polyoxyethylene fatty acid ester 32 easily fusible. This dispersion is sprayed on a granular excipient in a fluidized bed. The powder mixture thus formed is dispensed into pharmaceutical compositions after optional dilution with a pharmaceutically acceptable non-toxic inert carrier. The expression "easily fuse "here means that this ester melts below 80 ⁰ C and more particularly between 40 and 50 ⁰ C.

According to a preferred form of the invention, the polyoxyethylene 32 fatty acid ester used is a polyoxyethylene 32 distearate which melts at around 50 ^° C. to 60 ^° C. Polyoxyethylene distearate 32 is a product of the invention. commercially available. A product belonging to the same family is sold under the brand Kessco ® PEG 1540 DS (Stepan).

According to another preferred form of the invention, the granular excipient is an inert material such as cellulose, dextran, colloidal silica, vinylpyrrolidone polymers or copolymers, polyvinylpyrrolidones, acrylic polymers such as polycarbophil and similar products .

A preferred granular material is micro-crystalline cellulose and preferably the pharmaceutical quality marketed under the name AVICEL PH and in particular the quality sold under the name AVICEL PH 105.

The content of active ingredient dispersed in the polyoxyethylene fatty acid ester 32 may vary in large proportions because these esters are very good solvents. It is possible to perform both dilute solutions and concentrated solutions.

A preferred concentration of active ingredient varies from 30 to 50% of active ingredient in the fatty acid ester. Such contents allow easy entry into solution. A preferred concentration is that consisting of 40 to 50% of active ingredient.

Among the active ingredients that can be incorporated into the compositions according to the invention, mention may in particular be made of:

• anti-inflammatories and analgesics

salsalate

benorylate

Oxametacine indomethacin

Paracetamol

piroxicam

Tiénilique acid

Ethenzamide

Tramadol

• immunosuppressants Cyclosporine Tacrolimus

• antihistamines Terfenadine Brompheniramine Chlorpheniramine

• antifungals and anti-trichomonas Metronidazole

Ornidazole Dapsone Itraconazole Terbinafine

• antivirals Cytarabine Gancyclovir Acyclovir

• Antipsychotic Sulpiride Sultopride Amisulpride

• hormones

Estradiol and its esters (17β-valerate)

The Estrone

The estriol

Progesterone and its derivatives • cardiovascular and vasodilator agents Dobutamine

diltiazem

Nifedipine and analogues (Nitrendipine, Nisoldipine ...)

• Antiulcer agents Pirenzepine Ranitidine

Omeprazole Lansoprazole

• Antibacterial agents Erythromycin Flumequine Oxytetracycline Piperacillin Cefuroxime Amphotericin

• Propafenone anti-arrhythmic agents

amiodarone

Cordarone

flecainide

gallopamil,

verapamil,

dipyridamole,

Diisopyramide

• uricosuric agents Benzbromarone Probenecid

Suifinpyrazone Allopurinol

• Flunarizine antimigraine agents Derivatives of Ergotamine Sumatriptan

• Fluvoxamine antidepressant agents

Fluanisone Fluoxetine Paroxetine

• Flutamide anti-hormonal agents

• Bronchodilators Tulobutol Talinolol Prenalterol

• anxiolytic Thiothixene agents

trazodone

Doxepin

carbamazepine

• coronarodilators Ethaverine

Pentoxyphylline Eburnamonine

• Diuretics Furosemide

The Triamterene

The Torasemide

Hydrochlorothiazide

• antispasmodics Flavoxate Trimebutine Phlorogucinol • agents that inhibit the excretion of calcium Clodronate

Pamidronate Alendronate

• Pindione anticoagulants

Tromexan

analgesics Fentanyl, Dextropropoxyphene, Sufentanyl.

opiate derivatives Nalbuphine, Naltrexone, Dihydrocodeinone, Buprenorphine, or Methadone.

The invention finds particular use for the production of pharmaceutical forms whose bioavailability is greatly improved and whose active ingredient is an antilipemic agent and / or cholesterol-lowering agents. More specifically, the preparations based on derivatives of clofibric acid or fenofibric acid such as clofibrate, fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, pirifibrate or simfibrate. Mention may also be made of HMG coA reductase inhibitors (statins) such as Atorvastatin, Cerivastatin, Fluvastatin, Pravastatin and its sodium salt or Simvastatin, or triptans such as Sumatriptan or Frovatriptan.

In the particular case of clofibric acid derivatives, the advantage of a solvent such as a polyoxyethylene fatty acid ester 32 lies in the fact that this product is not likely to promote or produce a transesterification or to increase the toxicity of the active ingredient.

Another peculiarity of the present invention is to be able to produce bioavailable forms of hormonal products which are not or hardly absorbable in the digestive tract, such as progesterone, androsterone, chlormadinone acetate or Melengestrol. Usually, the alkylated derivatives are used in the 17α or 6α position to obtain digestive-active compounds (cyproterone, demegestone, promegestone, norethynodiol acetate, ethynyl estradiol). This substitution has the disadvantage of inducing annoying side effects (androgenic or anti-androgenic action, anti-estrogenic action and especially hepatotoxic effects) which are to be avoided in particular. This is why natural progesterone or its derivatives (dihydroprogesterone, 17α-hydroxyprogesterone) are often used, the latter being active digestive and not very toxic but less active than progesterone itself.

The dispersions according to the invention allow the production of pharmaceutical compositions containing, in addition to the active ingredient dispersed on the inert support, one or more pharmaceutically acceptable non-toxic inert excipients.

It will thus be possible to add the preparations obtained after incorporation in an inert material followed by fluidized bed drying, diluent, bulking agent, flavoring agent, coloring agent, disintegration, gelling agent, or a film-forming agent.

The content of active ingredient is calculated so that the final pharmaceutical formulation contains an effective and non-toxic active ingredient content. The amount of excipient is calculated so that the concentration of active fraction is of the order of 50%, that is to say, it does not exceed 50% and is preferably between 20 and 40%. A particular example is the preparation of pharmaceutical compositions based on fenofibrate absorbate in microcrystalline cellulose. In these compositions, the active ingredient content ranges from 50 to 150 mg per unit dose and preferably 60 mg, 90 mg or 130 mg of fenofibrate. The microcrystalline cellulose content varies from 40 to 60 mg per unit dose.

In the case of progesterone, it will be possible to produce pharmaceutical compositions whose active ingredient content ranges from 5 to 50 mg and in particular from 25 to 40 mg per unit dose.The content of polyoxyethylene distearate 32 will also be 5 to 100 mg per unit dose and the excipient content will also be between 5 and 100 mg.

Fenofibrate, progesterone or amiodarone preparations are provided hereinafter by way of example. They do not limit the invention.

Example I

Fenofibrate 25 g

Polyoxyethylene distearate 32 26 g

Microcrystalline cellulose 44 g

Magnesium Stearate 0.5 g The resulting mixture was divided into 1000 gelatin capsules containing 25 mg fenofibrate per unit dose.

Example II

Progesterone 30 g

Polyoxyethylene distearate 32 25 g

Microcrystalline cellulose 55 g

Malto dextrine 12 g

Calcium carbonate 5 g

Talc 5 g per 1000 capsules each containing 30 mg of progesterone.

Example III

Amiodarone 150 g IZ

Polyoxyethylene Distearate 32 180 g Polyvinylpyrrolidone 20 g

Colloidal silica 45 g

Rice starch 105 g per 1,000 tablets each containing 150 mg of Amiodarone.

The present invention also relates to the production of sublingual forms or oral tablets. They are intended to be placed under the tongue for sublingual tablets or glued to the palate for oral tablets. These types of tablets made according to the process of the invention show an even greater bioavailability.

These sublingual or oral tablets are made by the process according to the invention but the granular powdery product is then tabletted by adding a binding agent, a compressing agent and a slip agent.

Figures 1 to 4 show the results of pharmacokinetic studies carried out with compositions according to the invention for different active ingredients. The minimum efficiency concentration (MEC) is indicated for each of the compounds. In the following examples, the terms "formulation" and "preparation" are equivalent to the term "composition".

FIG. 1 is a graph showing the average blood concentration (in μg / ml) as a function of the resorption time after ingestion of the paracetamol tablets (in hours). For the formulation according to the invention, the results are obtained with a preparation based on 0.350 g of paracetamol produced according to the method of the invention. These results are compared with those obtained with commercial tablets containing the same dosage of paracetamol.

It can be seen in this figure that, in the case of the formulation according to the invention, the peak concentration is reached only 1 hour after ingestion of paracetamol tablets and that the maximum concentration (Cmax) is then 6.0 mcg / ml. This peak of blood concentration does not appear that after 4 hours with the commercial formulation and the maximum concentration (C'max) is then less than 4.0 μg / ml. Moreover, the CEM of paracetamol is reached in only 1/2 hour for the formulation of paracetamol according to the invention whereas this concentration is reached after 2 hours with the commercial formulation.

FIG. 2 is a graph showing the blood concentration (in μg / ml) as a function of the resorption time after administration of indomethacin (in hours). This figure represents the results obtained with a formulation prepared according to the method of the invention, and whose active ingredient is indomethacin, in comparison with the results obtained with a commercial formulation of indomethacin.

From the curves shown, the peak blood concentration for the formulation according to the invention appears rapidly since only 1 hour after the administration of indomethacin. In addition, the maximum concentration (Cmax) observed during this peak is 6 μg / mL for the formulation according to the invention. For the commercial formulation, it is necessary to wait 4 hours after the administration so that the peak of blood concentration is found and the maximum concentration (C'max) of the commercial formulation is then less than 4 μg / ml. In addition, the EMC of indomethacin is reached 3 hours after the administration of the formulation according to the invention whereas this concentration is never reached for the commercial formulation.

FIG. 3 is a graph showing the blood concentration (in μg / ml) as a function of the resorption time after administration of sumatriptan (in hours). The curves represent the results obtained with a composition according to the invention whose active ingredient is sumatriptan in comparison with those obtained with the commercial product.

It can be seen from this graph that the peak of blood concentration is reached only 1 hour after the administration of the composition according to the invention and the maximum concentration (Cmax) is then 3 μg / ml. In the case of the commercial product, the peak blood appears only 4 hours after the administration and the maximum concentration (C'max) is less than 2 μg / ml for this commercial product. Moreover, the CEM for sumatriptan is reached 3 hours after the administration of the composition according to the invention whereas with the commercial product this concentration is never reached.

FIG. 4 is a graph showing the plasma concentration (in μg / ml) as a function of the resorption time after oral administration of frovatriptan (in hours). The results are obtained from a preparation according to the invention, the active ingredient of which is frovatriptan. These results are compared with those obtained with the commercial formulation of this drug.

This figure shows that the peak concentration is reached only 1/2 hour after administration of the preparation according to the invention and the maximum concentration (Cmax) is then 7.5 μg / ml. For the commercial formulation, it is necessary to wait 2 hours to see appear peak concentration, the maximum concentration (C'max) being then less than 5 μg / ml. In addition, the EMF of frovatriptan is reached approximately 1 hour 30 after administration of the preparation according to the invention, whereas this concentration is never reached with the commercial formulation.

All these results show that in the case of the compositions according to the invention, the active ingredients are reabsorbed more quickly by the body and in greater quantities. Indeed, the resorption of the active ingredients is frankly facilitated by the compositions according to the invention and the Cmax concentrations obtained with the compositions according to the invention much higher than the C'max obtained with the similar products of commerce.

In addition, in the case of indomethacin, sumatriptan and frovatriptan, EMFs are never achieved with the commercial compositions. However, in the case of the compositions according to the invention, the EMFs are reached for each of the active ingredients presented in these examples. In addition, these concentrations are reached at most about 3 hours after administration of the compositions according to the invention. Thus, the compositions according to the invention allow not only a faster resorption but also to reach the concentrations of efficiencies in a short time in cases where these concentrations are not reached with the commercial compositions.

Claims

1. Process for producing water-soluble dry dosage forms, characterized in that one or more active ingredients are dispersed in a polyoxyethylene fatty acid ester 32, easily fusible, and then said dispersion is heated to a granular excipient in a bed. fluidized and distributes the powder mixture thus formed in pharmaceutical compositions after optional dilution with a pharmaceutically acceptable inert non-toxic excipient.

The process of Claim 1 wherein the polyoxyethylene 32 fatty acid ester is polyoxyethylene distearate 32.

The process of claim 1 or 2 wherein the polyoxyethylene fatty acid ester 32 melts below 80 ° C.

4. Method according to one of the preceding claims wherein the fatty acid ester of polyoxyethylene 32 is a polyoxyethylene distearate 32 whose melting is carried out at about 50 to 60 ^° C.

5. Method according to one of the preceding claims wherein the granular excipient is an inert material.

The method of claim 5 wherein the granular excipient is microcrystalline cellulose.

7. Method according to one of the preceding claims wherein the concentration of active ingredient (s) in the polyoxyethylene fatty acid ester 32, ranges from 30 to 50%.

8. Method according to one of the preceding claims wherein the amount of granular material per unit dose is calculated so that the concentration of active fraction is of the order of 50%.

9. Method according to one of the preceding claims wherein the active ingredient or mixture of active ingredients dispersed on the inert support, is (are) mixed with one or more inert excipients, non-toxic pharmaceutically acceptable for the purpose of to produce pharmaceutical compositions.

10. Method according to one of the preceding claims wherein the active ingredient is fenofibrate dissolved in polyoxyethylene distearate 32 and then dispersed on a support based on microcrystalline cellulose.

11. Method according to one of claims 1 to 9 wherein the active ingredient is progesterone dissolved in polyoxyethylene distearate 32 and then dispersed on a support based on microcrystalline cellulose.

12. Method according to one of claims 1 to 9 wherein the active ingredient a statin dissolved in polyoxyethylene stearate 32, and then dispersed on a support based on microcrystalline cellulose.

13. Method according to one of claims 1 to 9 wherein the active ingredient is paracetamol dissolved in polyoxyethylene distearate 32 and then dispersed on a support based on microcrystalline cellulose.

14. Method according to one of claims 1 to 9 wherein the active ingredient is an antimigraine product such as a triptan dissolved in polyoxyethylene distearate 32 and then dispersed on a support based on microcrystalline cellulose.

15. Method according to one of claims 1 to 9 wherein the water-dispersible form is a solution of Amiodarone in polyoxyethylene distearate 32 and then dispersed on a support based on micro-crystalline cellulose.

16. Method according to one of claims 1 to 9 wherein the active ingredient is buprenorphine or a salt thereof dissolved in polyoxyethylene distearate 32 and then dispersed on a support based on microcrystalline cellulose.

17. Process for producing pharmaceutical forms according to one of the preceding claims, in which the sublingual forms or oral tablets are produced.

18. Pharmaceutical compositions as obtained by the process according to any one of the preceding claims.