FR3059903A1 - ORAL MEDICINE COMPRISING AN OSMOTIC LAXATIVE INCORPORATED IN A MATRIX BASED ON VEGETABLE FATS - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition comprising: - between 30 and 55% by weight of said micronized and anhydrous macro gol pharmaceutical composition; and between 45 and 70% by weight of the pharmaceutical composition of a vehicle consisting of an anhydrous and hydrophobic fat-based lipid coating of plant origin with a melting point between 36 and 38 ° C, and its use as a laxative. Said vehicle protects the macrogol from the decrease in osmotic pressure originating from the humidity of the digestive tract.

Description

® FRENCH REPUBLIC

NATIONAL INSTITUTE OF INDUSTRIAL PROPERTY © Publication number:

(to be used only for reproduction orders)

©) National registration number

059 903

62128

COURBEVOIE © Int Cl ⁸ : A 61 K 31/765 (2017.01), A 61 K9 / 14, 47/44, 47/61, A 61 P 1/10

A1 PATENT APPLICATION

©) Date of filing: 08.12.16. (© Applicant (s): SALSARULO PHARMA Company to be- (30) Priority: limited liability - FR. @ Inventor (s): SALSARULO GERARD and SALSA- RULO GILLES. (43) Date of public availability of the request: 15.06.18 Bulletin 18/24. ©) List of documents cited in the report preliminary research: Refer to end of present booklet (© References to other national documents ® Holder (s): SALSARULO PHARMA Société à res- related: limited liability. ©) Extension request (s): (© Agent (s): GEVERS & ORES.

FR 3 059 903 - A1

ORAL MEDICINAL PRODUCT COMPRISING AN OSMOTIC LAXATIVE INCORPORATED IN A MATRIX BASED ON VEGETABLE FAT MATERIALS.

©) Oral medication comprising an osmotic laxative incorporated in a matrix based on vegetable fats

The present invention relates to an oral pharmaceutical composition comprising:

- between 30 and 55% by weight of said pharmaceutical composition of micronized and anhydrous macro gol; and

- between 45 and 70% by weight of the pharmaceutical composition of a vehicle consisting of an anhydrous and hydrophobic lipid coating based on a fatty compound of vegetable origin having a melting point of between 36 and 38 ° C, and at its use as a laxative.

The vehicle protects the macrogol from the decrease in osmotic pressure from moisture in the digestive tract.

i

Oral medication comprising an osmotic laxative incorporated in a matrix based on vegetable fats

The present invention relates to the field of laxative pharmaceutical preparations based on macrogol (PEG); it allows a significant reduction in daily doses of macrogol, thereby resulting in a reduction, or even almost disappearance, of the side effects resulting from high daily doses of this type of osmotic laxative.

The present invention is based on the incorporation of macrogol, also designated PEG in the following, in a hydrophobic matrix based on vegetable fats having a melting point at the temperature of the human body and more specifically between 36 ° C and 38 ° C, and its oral administration (for example in the form of gel or paste).

Osmotic laxatives, such as macrogol, are a class of water-absorbing laxatives, which lead to swelling and softening of the stool and can help treat the inconvenience of constipation.

The mechanism of action of this type of laxative however requires that it produce its effect at the level of the colon (recognized site of the action of osmotic laxatives), that is to say that it maintains a maximum osmotic pressure until 'to this action site; as a result, an optimal formulation is such that it avoids the contact of macrogol with the humidity of the digestive tract which decreases the osmotic pressure, base of the laxative efficiency of macrogol, and only releases macrogol in the colon.

A solution to this problem is proposed in European Patent Application EP 0 911 038 which describes a formulation of lactuose, another osmotic laxative, in a coating vehicle made up of a mixture of paraffinic hydrocarbons and which is not vegetable. ; this formulation makes it possible to reduce the doses of lactuose usually used, between 10 to 30 g per day for an adult, to 5 to 10 g per day for an adult and thus to reduce, even to avoid, the undesirable side effects of this type of active (bloating, flatulence, abdominal cramps) due to high doses of osmotic laxatives.

However, there is a prejudice against the medical use of paraffinic hydrocarbons because of their origin.

In addition, these paraffinic compounds themselves have a lubricating effect on the intestinal transit and actively contribute to the laxative effect of the composition.

Various documents describe the use of macrogol:

For example, PCT International Application WO 2013/044085 describes solid laxative compositions in the form of bars, chocolate for example, or candies; the objective of this type of formulation is to mask the taste of active ingredients. It should be noted that the formulations exemplified in this document include hydrophilic ingredients (salts, sucralose, milk powder present in white chocolate) and water which do not make it possible to preserve the anhydrous character of the macrogol up to its site. action; in addition, there is nothing to suggest that the vehicle of the proposed formulations has a melting point between 36 and 38 ° C.

Other publications, such as the clinical journal "Osmotic and stimulant laxatives for the management of childhood constipation" by Gordon et al. (A COCHRANE REVIEW JOURNAL, vol. 8, n ° l, 01/01/2013, p. 57-109) which compiles data from various clinical laxative trials or the article “A randominsed, double-blind study of polyethylene glycol 4000 and lactulose in the treatment of constipation in children "by Treepongkaruna et al. (BMC PEDIATRICS, BIOMED CENTRAL, LONDON, GB, vol. 14, no.1, 19/06/2014, p. 153) which describes a study comparing the effect of daily administration of 3.3 g of lactulose or 8 g of PEG for the treatment of constipation in children, propose the administration of low daily doses of macrogol but these are pediatric doses which, relative to the weight of the patient to be treated, correspond to conventional doses, c that is to say too high and which induce undesirable side effects.

However, none of these documents proposes a dosage of this laxative which is sufficiently effective to be able to reduce the daily doses of macrogol administered.

The Applicant has thus set itself the objective of developing a laxative drug for the treatment of constipation making it possible to reduce the daily doses of PEG to lessen the side effects resulting from the administration of large doses of laxative and has developed a new galenic formulation of PEG based on vegetable and non-paraffinic compounds:

which preserves the entire osmotic pressure of PEG, the basis of its laxative effect, up to its site of action, the colon;

who is insensitive to the pH values of the digestive tract;

which surprisingly allows the use of reduced doses of

PEG, between 5 and 15g / day, that is to say as low as in the case of the use of a paraffinic vehicle, and resulting in the significant reduction of undesirable side effects (abdominal cramps, bloating, flatulence ..,);

whose vehicle is mainly of vegetable origin.

The Applicant has achieved this result by using, as a vehicle, an anhydrous and hydrophobic lipid coating composed of waxes or butters of plant origin, optionally added with vegetable oils to obtain a melting point of between 36 and 38 ° C; surprisingly, this vehicle, which is based on a particular selection of excipients conventionally used for the formulation of medicaments, advantageously increases the effectiveness of macrogol and allows the use of reduced daily doses of macrogol.

French Patent Application FR 2 852 843 describes pharmaceutical formulations consisting of solid lipid particles obtained by a particular preparation process for the formation of lipid droplets in a gel; there is no question in this Patent Application of seeking to reduce the doses of active principle. The purpose of this Patent Application is to develop a specific manufacturing process using lipid droplets and resulting in formulations allowing the masking of the taste of active ingredients; this Request contemplates the use of an extensive list of fatty excipients including non-vegetable excipients. In addition, the preparation of these solid forms requires the implementation of a more complex process than that allowing the preparation of the pharmaceutical composition according to the invention.

More specifically, the oral pharmaceutical composition according to the invention aims to maintain the osmotic pressure of macrogol during its oral administration, hence the reduction in the daily dosage of this laxative and comprises:

between 30 and 55% by weight of the pharmaceutical composition of anhydrous macrogol; the macrogol can be micronized, in this case, the particle size is preferably between 75 and 150 μm; and between 45 and 70% by weight of the pharmaceutical composition of a vehicle consisting of an anhydrous and hydrophobic lipid coating based on fatty compounds of plant origin; more particularly, this anhydrous and hydrophobic lipid coating is composed:

* or up to 100% by weight of the vehicle when it is shea butter and / or cocoa butter; or * either from 12 to 25%, preferably from 15 to 25%, by weight of the vehicle of a vegetable wax; and, depending on whether it is vegetable butter or vegetable wax, from 25 to 88%, preferably from 25 to 85%, by weight of the vehicle of a vegetable oil making it possible to adjust the melting point of said vehicle between 36 and 38 ° C.

By osmotic and anhydrous laxative is meant powdered macrogol which contains less than 0.5% water.

The fatty compounds of vegetable origin of the anhydrous and hydrophobic lipid vehicle are chosen from a specific selection of products commonly used by those skilled in the art for hydrophobic coatings, with controlled melting temperature such as camauba wax, candelilla, rice bran wax, shea butter, cocoa butter or other pharmaceutically acceptable vegetable wax.

In order to reach a melting point of 36 to 38 ° C, some waxes and some butters require the addition of anhydrous and hydrophobic vegetable oil such as sunflower oil, rapeseed oil, corn oil , linseed oil or their mixture.

If it is desired to improve the homogeneity of the composition according to the invention, the anhydrous and hydrophobic lipid vehicle can also comprise certain plant or non-plant compounds such as, for example, glycerides and / or glycerostearates.

The melting point of the anhydrous and hydrophobic lipid vehicle can be conventionally measured with a variability of +/- 5% by using the technique described in the current French Pharmacopoeia or by a similar method.

The composition according to the invention is in the form of a paste or gel to be administered orally.

To facilitate taking up the composition according to the invention, the anhydrous and hydrophobic lipid vehicle can comprise one or more flavors and / or sweeteners conventionally used in pharmaceutical compositions.

The anhydrous and hydrophobic lipid vehicle can also comprise an emulsifier, such as for example glycerostearates and cholesterol and / or a fluidizer, such as for example dimethicone (polydimethylsiloxane).

All the additional excipients used must necessarily be anhydrous in order to preserve the osmotic potential of the incorporated osmotic laxative.

The excipients of the composition are such that they do not include a cellulose derivative which would have the undesirable effect of capturing the water present along the digestive tract resulting in a decrease in the osmotic pressure of the macrogol.

According to a particular embodiment of the present invention, the oral pharmaceutical composition consists of:

between 30 and 55% by weight of the pharmaceutical composition of anhydrous macrogol; the macrogol can be micronized, in this case, the particle size is preferably between 75 and 150 μm; and between 45 and 70% by weight of the pharmaceutical composition of a vehicle consisting of an anhydrous and hydrophobic lipid coating based on fatty compounds of plant origin; more particularly, this anhydrous and hydrophobic lipid coating consists of:

* or up to 100% by weight of the vehicle when it is shea butter and / or cocoa butter; or * either from 12 to 25%, preferably from 15 to 25%, by weight of the vehicle of a vegetable wax; and, depending on whether it is vegetable butter or vegetable wax, from 25 to 88%, preferably from 25 to 85%, by weight of the vehicle of a vegetable oil making it possible to adjust the melting point of said vehicle between 36 and 38 ° C;

- between 0 and 5% by weight of the pharmaceutical composition of an excipient chosen from fluidizers, agents improving the homogeneity of the composition, flavors, sweeteners and / or emulsifiers.

The Applicant has been able to demonstrate that, when the oral pharmaceutical composition according to the invention is administered, the anhydrous and hydrophobic lipid vehicle isolates and protects the macrogol from humidity in the digestive tract; macrogol thus retains its osmotic pressure close to 100% at the start, thus reducing the dosage. It is recalled that the colon is the commonly recognized place for the effectiveness of osmotic laxatives.

The anhydrous and hydrophobic lipid coating ratio on active ingredient is adapted to withstand gastric emptying time in order to obtain optimal disintegration and the release of macrogol at the level of the colon, without the macrogol being in direct contact with the humidity of the tract digestive which would have the effect of lowering its osmotic pressure before reaching the colon.

The present invention advantageously relates to a use of the composition according to the invention as a laxative, in particular for the treatment of constipation, preferably in adults; thanks to this optimized formulation, this use is such that the macrogol is administered in an amount representing a reduced daily dosage, of between 5 to 15 g per day for an adult, unlike existing macrogol-based drugs whose dosage varies between 10 and 30 g per day.

According to a particular embodiment, the vehicle is composed of a vegetable wax added with a vegetable oil; the oral pharmaceutical composition according to the invention then consists of:

Active ingredient: macrogol from 45.00 to 55.00 g

Excipient:

Vegetable wax from 6.00 to 11.00 g, preferably from 9.00 to 11.00 g

Vegetable oil from 32.00 to 37.00 g

Optionally, uniformity improving agent from 1.80 to 1.90 g

Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 1.60 to 1.80g

According to a more specific embodiment, the oral pharmaceutical composition according to the invention consists of:

Active ingredient: macrogol from 45.00 to 55.00 g

Excipient:

Camauba wax from 6.00 to 11.00 g, preferably from 9.00 to 11.00 g Corn oil from 32.00 to 37.00 g

Optionally, glyceryl stearate from 1.80 to 1.90 g

Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 1.60 to 1.80g

The macrogol is a micronized or non-micronized macrogol, of the 4000 or 3350 type.

This type of composition is prepared by first mixing the vegetable wax and the vegetable oil in a heating bath at about 90 ° C; the mixture is then cooled to around 75 ° C and the glyceryl stearate is optionally added; the other excipients are then added; the whole is stirred until a homogeneous mixture is obtained; the mixture is cooled to approximately 45 ° C. and the active principle is added with mixing.

According to another particular embodiment, the vehicle is composed of vegetable butter and, optionally vegetable oil; the oral pharmaceutical composition according to the invention then consists of:

Active ingredient: macrogol from 35.00 to 50.00 g, preferably from 35.00 to 45.00 g

Excipients:

Vegetable butter (shea and / or cocoa) from 55.00 to 65.00 g

Other excipients such as fluidifier, emulsifier, flavorings and / or sweeteners from 35.00 to 45.00 g from 2.00 to 5.00 g, preferably from 2.00 to 4.00 g According to another embodiment , the oral pharmaceutical composition according to the invention consists of:

Active ingredient: micronized macrogol Excipients:

Vegetable butter (shea and / or cocoa)

Vegetable oil from 30.00 to 50.00 g from 15.00 to 25.00 g sweeteners from 2.00 to 5.00 g.

Other excipients such as fluidifier, emulsifier, flavorings and / or

According to yet another embodiment, the oral pharmaceutical composition according to the invention consists of;

Active ingredient ; macro gol Excipients:

Shea butter Cocoa butter Corn oil

Other excipients such as sweeteners from 35.00 to 45.00 g from 30.00 to 50.00 g from 3.00 to 10.00 g from 15.00 to 25.00 g fluidizer, emulsifier, flavors and / or 2.00 to 5.00 g, preferably 2.00 to 4.00 g

The macrogol is a micronized or non-micronized macrogol, of the 4000 or 3350 type.

This type of composition is prepared by melting the vegetable butters at a temperature between 45 and 50 ° C, then incorporating the oil, then adding and mixing the micronized active ingredient and any other excipients.

The present invention also relates to the use of an anhydrous and hydrophobic vehicle having a melting point between 36 and 38 ° C consisting of fatty compounds of vegetable origin having a melting point between 36 and 38 ° C such as defined above and optionally, up to 5% by weight of an excipient chosen from thinners, homogeneity improving agents, emulsifiers, flavors and / or sweeteners; to preserve the osmotic pressure from macrogol to the colon. By “preserving the osmotic pressure of the macrogol”, it is meant keeping the macrogol in an anhydrous state (water content less than 0.5%) until it reaches the colon, this goal is obtained thanks to the lipid vehicle anhydrous and hydrophobic which prevents the macrogol from being in contact with the humidity of the digestive tract which lowers its osmotic pressure, hence the reduction in the dosage of the macrogol in the composition according to the invention.

EXAMPLES

Examples of compositions according to the invention

Composition IA

Active ingredient: macrogol 4000 micronized 50.00 g

Excipient:

Camauba wax

9.65g

Corn oil 36.70g

Glyceryl stearate 1.87g

Other excipients 1.78g (Cholesterol, aroma, aspartame)

Composition IB

Active ingredient: macrogol 4000 mcronized 50.00 g

Excipient:

Camauba wax 6.20g

Corn oil 38.70g

Glyceryl stearate 1.87g

Other excipients 3.23g (Cholesterol, flavor, aspartame)

Composition 2A

Active ingredient: macrogol 3350 55.00 g

Excipients:

Camauba wax 9.35 g

Sunflower oil 33.87g

Other excipients 1.78g (Flavor, emulsifier, sweetener)

Composition 3A

Active ingredient: macrogol 4000 micronized 35.00 g

Excipients:

Shea butter 62.00 g

Other excipients 3.00 g (Flavor, emulsifier, sweetener, fluidizer)

Composition 3B

Active ingredient: macrogol 4000 micronized 40.00 g

Excipients:

ίο

Shea Butter 35.00 g Cocoa butter 5.00 g Corn oil 17.00 g Other excipients 3.00 g (Flavor, emulsifier, sweetener, fluidifier)

Claims (11)

1. Oral pharmaceutical composition intended to maintain the osmotic pressure of macrogol during its oral administration, consisting of: between 30 and 55% by weight of said pharmaceutical composition of anhydrous macrogol; and between 45 and 70% by weight of the pharmaceutical composition of a vehicle consisting of an anhydrous and hydrophobic lipid coating based on fatty compounds of plant origin having a melting point of between 36 and 38 ° C; - between 0 and 5% by weight of the pharmaceutical composition of an excipient chosen from thinners, homogeneity-improving agents, emulsifiers, flavors and / or sweeteners. 2. Oral pharmaceutical composition according to claim 1, characterized in that said anhydrous lipid coating consists of: * or up to 100% by weight of the shea butter and / or cocoa butter vehicle; or * either from 12 to 25%, preferably from 15 to 25%, by weight of the vehicle of a vegetable wax; and, depending on whether it is vegetable butter or vegetable wax, from 25 to 88%, preferably from 25 to 85%, by weight of the vehicle of a vegetable oil making it possible to adjust the melting point of said vehicle between 36 and 38 ° C. 3. Oral pharmaceutical composition according to claim 1 or claim 2, characterized in that said osmotic laxative is micronized with a particle size between 75 and 150 µm or non-micronized. 4. Oral pharmaceutical composition according to any one of claims 1 to 3, characterized in that the vegetable wax is camauba wax, candelilla wax, rice bran wax, or another pharmaceutically acceptable vegetable wax. 5. Oral pharmaceutical composition according to any one of the preceding claims, characterized in that the vegetable oil is chosen from sunflower oil, rapeseed oil, corn oil, linseed oil or their mixed, 6. Oral pharmaceutical composition according to any one of the preceding claims, characterized in that it consists of: Active ingredient: macrogol from 45.00 to 55.00 g Excipient: Vegetable wax from 6.00 to 11.00 g Vegetable oil from 32.00 to 37.00 g Homogeneity improving agent from 1.80 to 1.90 g Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 1.60 to 1.80 g. 7. Oral pharmaceutical composition according to any one of the preceding claims, characterized in that it consists of: Active ingredient: macrogol from 45.00 to 55.00 g Excipient: Camauba wax from 6.00 to 11.00 g Corn oil from 32.00 to 37.00 g Optionally glyceryl stearate from 1.80 to 1.90 g Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 1.60 to 1.80 g. 8. Oral pharmaceutical composition according to any one of claims 1 to 3 or 5, characterized in that it consists of: Active ingredient: micronized macrogol from 35.00 to 45.00 g Excipients: Vegetable butter (shea and / or cocoa) from 30.00 to 50.00 g Vegetable oil from 15.00 to 25.00 g Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 2.00 to 5.00 g. 9. Oral pharmaceutical composition according to claim 8, characterized in that it consists of: Active ingredient: micronized macrogol from 35.00 to 45.00 g Excipients: Shea Butter Cocoa butter Corn oil from 30.00 to 50.00 g from 3.00 to 10.00 g from 15.00 to 25.00 g Other excipients such as fluidifier, emulsifier, flavors and / or sweeteners from 2.00 to 5.00 g. 10. An oral pharmaceutical composition according to any one of the preceding claims, retaining the osmotic pressure of macrogol, for its use as an osmotic laxative for the treatment of constipation in adults. 11. Use of a vehicle consisting of an anhydrous and hydrophobic coating, itself consisting of fatty compound of vegetable origin having a melting point between 36 and 38 ° C to preserve the osmotic pressure of the macrogol 10 to the settler.