WO2023105397A1

WO2023105397A1 - Tablets comprising chondroitin sulphate, glucosamine hydrochloride, and vitamin c for the treatment of cartilage, tendon, bone damages

Info

Publication number: WO2023105397A1
Application number: PCT/IB2022/061810
Authority: WO
Inventors: Giovanni Gennari; Monica Campisi
Original assignee: Fidia Farmaceutici S.P.A.
Priority date: 2021-12-09
Filing date: 2022-12-06
Publication date: 2023-06-15
Also published as: IT202100030935A1

Abstract

Chewable and/or suckable tablets comprising, or consisting of, sodium chondroitin sulphate, glucosamine hydrochloride, Vitamin C, and excipients, characterized in that the excipients comprise sorbitol and xylitol in a weight ratio between 1 : 1.4 and 1:2, respectively, are described. The tablets of the invention are stable and show optimal organoleptic characteristics.

Description

TABLETS COMPRISING CHONDROITIN SULPHATE, GLUCOSAMINE HYDROCHLORIDE, AND VITAMIN C FOR THE TREATMENT OF CARTILAGE, TENDON, BONE DAMAGES

Object of the invention are nutraceutical compositions in the form of chewable and/or suckable tablets comprising, or consisting of, sodium chondroitin sulphate, glucosamine hydrochloride, Vitamin C, formulated with specific excipients. Such tablets contribute significantly at maintenance of articular health and are useful in the prevention and treatment of cartilage, tendon, bone damages due to age, overweight, pathologies, in particular osteoarthrosis, and also, in younger subjects, to intense and hard sport practices.

Background art

The use of saccharides and polysaccharides, and in particular of chondroitin sulphate (CS) and glucosamine, in the prevention and treatment of cartilage damages of different origin, is known. In fact, they constitute the fundamental bricks for the tridimensional structuration of the matrix and participate actively at the maintenance of the functionality and integrity of the articular tissue, and in particular of cartilage.

In detail, CS, as a component of proteoglycans, contributes to the elasticity of the articular cartilage, being the major responsible of its compressive strength. Also, it seems being implied in the production of the cartilage itself; further, CS shows a demonstrated anti-inflammatory effect, which also can help to reduce the articular swelling and pain and to slow the wear process of the articular cartilage (Bruy ere, Exp Opin Pharmacother, 2018, 19, 409-412).

Glucosamine (Glu) is an amino saccharide precursor of glycosaminoglycans (GAGs), main constituents of the articular cartilages and synovial fluid, and of which it stimulates the synthesis, thus bringing its contribution to the health of the cartilage itself and of the joint in toto (Nagaoka et al., Int J Biol Macromol, 2019, 132, 795-800).

Considering properties and biological roles, it is understood as since a long time that the supplementation with such substances is indicated to strengthen the articular cartilage and protect it from the damages caused by specific pathologies such as osteoarthrosis or wear induced by mechanical deterioration (Kelly, Altern Med Rew, 1998, 3, 27-39; Mantovani et al., Curr Med Chem, 2016, 23, 1139-51).

Very often CS and Glu are associated to other active ingredients such as mineral salts (selenium, calcium, zinc, manganese), natural extracts (Boswellia, Devil's claw), fatty acids (lipoic acid), adenosylmethionine, methyl sulphonylmethane, hyaluronic acid, collagen, vitamins (EP2948160, EP1408988, EP1849471). Among the latter, particularly used are Vitamin D, mostly for female subjects in postmenopausal age due to its beneficial effect on bone metabolism, and Vitamin C that, due to its antioxidant activity, neutralizes free radicals and helps to extinguish the inflammatory cascade thus giving a significative synergic contribution to the action of CS and Glu. Further, Vitamin C is able to increase collagen synthesis, thus contributing to the integrity and health of bones and articular cartilage (DOI: 10.1016/s0945-053x(01)00193-7; DOI: 10.1177/2325967118804544).

Generally, the compositions containing CS and Glu, in association to suitable excipients and possible other substances, are in the form of tablets or capsules to be swallowed or powders to be suspended in water. The doses to be administered with preventive/therapeutic purpose are quite high, up to 1200 mg/die for chondroitin sulphate and up to 1500 mg/die for glucosamine. If to these dosages the excipients required for the formulation of the composition are added, and possibly other active ingredients, it is understood easily that the tablets or capsules or powders to be assumed, even if divided in multiple daily administrations, have an important volume; with regards to powders, since CS, differently from Glu, is poorly water-soluble, they tend to have a rather unpleasant pasty texture.

The combination of these factors influences negatively the patient compliance in particular for elderly patients with chewing difficulties, or dysphagic or edentulous.

Also, if considering that the therapies of interest are developed in the medium to long term, it is even better understood how important it is administering such active ingredients, even at the highest dosages and in association with other substances, in a suitable, easy, and pleasing to the patient pharmaceutical form, such as a chewable tablet.

From the point of view of the pharmaceutical technique, chewable tablets belong to the larger class of “tablets,” i.e., solid preparations, each containing a single dose of one or more active ingredients, and they are obtained by direct compression of a powder or a mixture of powders as such or previously granulated, in relation to the nature of the components.

Briefly, powders can be granulated according to different techniques, such as: dry granulation: it transforms a powder into a granulate without using moisture and heat, with the aid of a non-aqueous binder, by powder compression and subsequent grinding of the obtained masses, to obtain granules of the desired size. It is suitable for active ingredients which are thermo-sensitive or unstable in an aqueous solution; wet granulation: a liquid (water or, more often, mixtures of water/organic solvent, such as ethanol) wherein a binder (sugars, gelatin, starch, polyvinylpyrrolidone, cellulose derivatives, etc.) can be dissolved is added to powders: the thus obtained mass is forcibly passed through a sieve with pores of the size of the granules to be obtained and the aggregating liquid is evaporated successively by heating. This is the most used technique for the preparation of chewable tablets (Pharmaceutical Technology 4,

fluid-bed granulation: it consists in fluidization of a powder bed on which a binding liquid is sprayed from above; the wet particles become slightly sticky and colliding with other particles, agglomerate forming a granule. As in the previous case, the aggregating liquid is evaporated by heating the granulate. This is a very fast and widely used technique for the production of mixtures for sticks and sachets, i.e., for high flowing granulates which do not provide for compression; further, it has a lot of variables to be controlled and it is not useful for oxidable substances and for very thin or low-density powders.

Regardless of technique, any tablet has to satisfy specific requirements, described in the International Pharmacopeias, such as dosage and content uniformity, mass uniformity, suitable mechanical resistance to avoid damages during the extraction from blister and handling.

Beside these characteristics, the chewable tablets have to be enough resistant for the already mentioned reasons, but crushable without much difficulty, precisely by simple chewing. Another fundamental characteristic of chewable tablets is the taste: in fact, a bad taste can prejudice the compliance of the patient, who will tend to avoid to assume the product, and therefore bad taste has to be masked.

In general, all these requirements are fulfilled inserting in the composition a wide range of excipients, such as sweeteners, flavors, taste masking agents, disaggregants, etc., each one with its own specific features. This generates a chewable tablet containing a high number of excipients (Nyamaweya, Pharm Techno! . 2020, 44, 38-44), potentially interfering with a correct release of the active ingredients and with the mechanical properties of the tablets themselves.

Some attempts to overcome these issues are known. For example, EPl 570842 discloses CS- and Glu-based solid chewable formulations, characterized from a huge water content required to keep together the mass. In fact, according to the inventors, dry compositions such as the classic CS- and Glu-based chewable tablets (prepared, for example, as in CN104707127 and CN 1899300) are not suitable in this kind of therapy, since the patient tends to swallow them as soon as crushed and moisturized with saliva, therefore before the total release of the active ingredients in the oral cavity: this latter aspect has to be kept in consideration because the absorption of the active ingredients can start already through the oral mucosa, during chewing.

The present invention overcomes the state of the art by making a tablet comprising, or consisting of, chondroitin sulfate, glucosamine hydrochloride, and Vitamin C, and specific excipients, which can be indifferently be chewed or sucked, thus making the intake very simple, and without compromising the correct release of the active ingredients. The tablets, object of the invention, are also characterized by an excellent palatability, total masking of the taste of the active ingredients and a small size. Such results are obtained by the choice of specifically calibrated excipients and a specially studied production process. Description of the invention

The invention relates to chewable and/or suckable tablets comprising, or consisting of, sodium chondroitin sulphate, glucosamine hydrochloride, for sake of brevity defined glucosamine, Vitamin C (L-ascorbic acid), and specific excipients, in particular sorbitol and xylitol, offering the following advantages:

• ensuring dosage, content, and mass uniformity;

• being adequately resistant from the mechanical point of view so to be handled;

• being chewable but also suckable, therefore suitable for dysphagic or edentulous patients with chewing difficulties;

• not requiring to be assumed with liquids;

• being pleasant to palate, in terms of taste and sensation;

• being formulated with a limited number of excipients, thus not interfering with the release of the active ingredients;

• having a small size with respect to the amount of the contained active ingredients;

• being free from lactose and gluten, thus suitable for intolerants.

The tablets of the invention, due to the combined action of the active ingredients, contribute significantly to maintenance of articular health and are useful in the prevention and treatment of cartilage, tendon, bone damages due to age, overweight, pathologies, in particular osteoarthrosis, and also, in younger subjects, to intense and hard sport practices.

With regard to the active ingredients, CS is isolated traditionally from bovine, avian, or fish cartilage. More recently, CS production process has been set up by bacterial fermentation, allowing to obtain a purer product, free from biological pollutants (proteins, viruses, etc.) and with uniform chemical-physical characteristics (EP 2852437). Even for Glu, which is obtained normally by means of extraction by hydrolysis from the exoskeleton of crustaceans, fermentation processes have been developed that, as for CS, produce a uniform, pure, equivalent to the extractive one, starting material (EP 1095158, EP 3441473). The fermentation processes have a minor environmental impact with respect to the extractive ones and therefore are desirable from the industrial point of view. Finally, with regard to Vitamin C, it can be produced according to the classic chemical -fermentative method (Reichstein method, US 2265121; US 2301811) or according to the fermentative route completely, with the aid of specifically engineered bacteria (Erwinia herbicola and Corynebacterium) (DOI: 10.1007/978-94-007-5055-5_12; https://ioumals.asm.Org/doi/10.1128/aem.54.7.1770-1775.1988).

Regardless of the production process, the industrial Vitamin C is completely identical to the one normally present in nature: very often, to reduce oxidation and thus promote stability in pharmaceutical compositions, it is used in its “coated” form, /.< ., in the form of microgranules coated with ethyl cellulose, and this is the preferred form used by the Applicant.

In the scope of the present invention the starting materials can derive from any source and, for CS and Glu, preferably from a fermentative source: in this case the tablets of the invention are suitable for those who have allergy problems or particular sensibilizations, or for those who chose, as a life style, of not assuming food, or in general substances, deriving from animals.

The active ingredient content of each tablet can vary, and precisely:

• glucosamine 200 to 300 mg, preferably 250 mg/tablet;

• CS 150 to 250 mg, preferably 200 mg/ tablet;

• Vitamin C 100 to 200 mg, preferably 140 mg/ tablet.

In percentage values, such dosages correspond to:

• glucosamine between 14 and 22%, preferably between 17 and 18% by weight/tablet;

• chondroitin sulphate between 10 and 20%, preferably between 14 and 15% by weight/tablet;

• Vitamin C between about 7 and 14%, preferably equal to 10% by weight/tablet.

With regards to excipients, their combination in qualitative and quantitative terms was studied deeply, calibrating it to obtain, after a set up specifically production process, chewable tablets able to satisfy not only the specifications described in the International Pharmacopoeias, but also the chewiness and palatability requirements, so to be efficacious but also easy to assume and pleasant. The excipients used herein are known, but in the scope of the invention herein described they are used in modes not experimented previously in the fluid-bed granulation.

In fact, the Applicant has verified, after a long test series, that the standard technique for the chewable tablets, /.< ., the wet granulation of powders and the subsequent compression of the granulate, was not satisfying: due to interaction between Glu and CS (the latter used as binder), grumes and spots were formed on the tablet surface, compromising the aesthetic, palatability and, mostly, dosage uniformity. The Applicant made further attempts, making use of direct compression of powders or dry granulation, without success. In the first case too fragile and friable tablets were obtained, not suitable for the packing step, not suitable for chewing and even not compliant to the Pharmacopoeia standards.

In the second case, the dry granulation compromised seriously the subsequent compression step, giving origin to tablets not suitable absolutely for the use herein expected.

Instead, the Applicant has surprisingly found to be unexpectedly efficacious for the invention the mandatory presence in the composition of sorbitol and xylitol in a specific weight ratio between them. Precisely, the ratio sorbitol :xylitol can be 1 :2, preferably is 1 : 1.4.

Only when the ratios between sorbitol and xylitol are respected, using a very low number of further excipients, a modified operatively with respect to the standard fluid-bed granulation can be made, by the mixing of active ingredients and excipients according to a specific order.

All the active ingredients, specifically studied excipients and production process allow to obtain chewable and/or suckable tablets satisfying all the needed requirements.

Beside sorbitol and xylitol in the described ratios, the further used excipients are: • a sweetener, preferably sucralose;

• anti-agglomerating agents, preferably magnesium salts of fatty acids (stearate) and silica dioxide;

• natural flavors, both in the form of powder and microcapsules.

It is known that fluidized bed granulation is not suitable to produce chewable tablets since, requiring heating to eliminate the aqueous part, it can alter the stability, besides that of active ingredients, also of flavors, thus compromising the covering of unpleasant odors and taste.

Instead, the chewable tablets, object of the invention, were made exactly with this technique, subjecting to fluidized bed granulation only a selected suitably percentage of the powders (active ingredients and excipients): precisely, the entire dose of Vitamin C, between 90 and 95% of glucosamine, the entire dose of xylitol and a portion of sorbitol were granulated, using an aqueous solution as agglomerating agent wherein the remaining 5-10% of glucosamine is dissolved.

The granulate thus obtained after drying is then mixed, according to a well-defined order, with CS and the remaining excipients (the remaining portion of sorbitol, a sweetener, anti-agglomerating agents), and with flavors, which, not being subjected to the drying that the fluid-bed requires, keep their fragrance perfectly unaffected, and provide for a total and perfect covering of unpleasant taste and odors.

In this way, the active ingredients and the excipients are not subjected to alterations and the resulting tablets respond perfectly to the needed requirements; for this reason, the described invention represents a neat overcoming of the prior art.

Briefly, the preparation process of the tablets comprises or consists of the following steps: a) fluid-bed granulation of a part of active ingredients and a selection of excipients; in this step are mixed and sieved subsequently:

1. Vitamin C, in amounts preferably equal to 10% of the weight expected in the final tablet;

2. a percentage of sorbitol, between 85 and 90% of its total weight expected in the final tablet;

3. a percentage of xylitol, preferably equal to 30% of the weight of the final tablet;

4. a percentage of glucosamine between 90 and 95%, preferably 93%, of the total weight expected in the final tablet.

The binding solution is consisting of depurated water wherein the remaining portion of glucosamine was dissolved; the water amount is equal to 4 times the weight of glucosamine to be dissolved. At the end of the granulation step, the drying and sieving steps are carried out and then b) mixing of the obtained granules with the remaining ingredients (active ingredients and excipients): the granules obtained from step a) are mixed in this order with

1. chondroitin sulphate in an amount preferably comprised between 14 and 15% of the weight of the final tablet;

2. a sweetener, preferably sucralose;

3. powdered flavors;

4. an anti-agglomerating agent, preferably silica dioxide;

5. flavors in a microencapsulated form;

6. the remaining percentage of sorbitol, between 10 and 15% of the total weight expected in the final tablet.

After suitable mixing and further sieving a second anti-agglomerating agent is added, preferably magnesium stearate, and, after further mixing c) pressing of the mixture resulting from step b) is carried out, by a compressing machine to give tablets of the desired shape and size.

In the preferred embodiment, the tablets weight 1.4 g and contain 420 mg/tablet of xylitol. The excipient doses can vary in relation to the active ingredient amounts.

Example 1: preparation of tablets containing glucosamine hydrochloride 250 mg, sodium chondroitin sulphate 200 mg, L-ascorbic acid 140 mg.

Each 1.4 g tablet contains:

Step a)

L-Ascorbic acid, xylitol, 89% of total sorbitol and 93% of total glucosamine are mixed, sieved on steel vibrating screen and harvested in the fluid-bed basket. In a suitable dissolver loaded with purified water the remaining 7% of glucosamine is added, keeping under stirring up to complete dissolution, and thus obtaining the aggregating solution. The water amount is equal to 4 times the weight of glucosamine to be dissolved. The dissolver is then connected to the fluid-bed and the previously prepared aggregating solution is sprayed on the powder mixture. At the end of the spraying step, the drying of the granules and the sieving thereof on the vibrating screen is carried out. Step b)

The thus obtained granules are further mixed with sodium chondroitin sulphate, sucralose, lemon and lemon-lime flavors, silica dioxide, lemon essential oil and finally the remaining portion of sorbitol, equal to 11% of the expected total amount. After suitable mixing and sieving, magnesium stearate is added to the thus obtained entire amount and the mixing is carried out for further 2 minutes.

Step c)

The mixture resulting from step b) is directed to the compressing machine producing round tablets, with 15 mm diameter, 5 mm thickness and 1.4 g weight each.

The thus obtained tablets respond perfectly to the criteria set from European Pharmacopoeia (European Pharmacopoeia 10.0) both for tablets in general, z.e., dosage, content, mass uniformity, and mostly for chewable tablets (hardness between 10 and 12 Kp and friability < 0.5%), resulting as easily crushable with simple chewing but enough resistant to allow relative handling both at industrial level and mostly at patient side.

The tablets shall be assumed daily, in relation to the individual needs and according to physician modes and indications: in general, for the tablets containing Glu 250 mg, CS 200 mg, and Vitamin C 140 mg, two tablets/die are advised, better if in a single administration, to be chewed or dissolved slowly in the oral cavity. They find application in the prevention and treatment of cartilage, tendon, bone damages due to age, overweight, pathologies, in particular osteoarthrosis, and also, in younger subjects, to intense and hard sport practices.

Claims

1. Chewable and/or suckable tablets comprising, or consisting of, sodium chondroitin sulphate, glucosamine hydrochloride, Vitamin C, and excipients, characterized in that the excipients comprise sorbitol and xylitol in a weight ratio between 1 : 1.4 and 1 :2, respectively.

2. Tablets according to claim 1 wherein the sorbitol :xylitol ratio is 1 : 1.4.

3. Tablets according to claim 1 comprising unit doses of 200 to 300 mg of glucosamine hydrochloride, preferably 250 mg/tablet, 150 to 200 mg of chondroitin sulphate, preferably 200 mg/tablet, and 100 to 300 mg of Vitamin C, preferably 140 mg/tablet.

4. Tablets according to claim 1, 2 or 3 further comprising sweeteners, flavors, antiagglomerating agents.

5. Tablets according to claim 4 wherein the sweetener is sucralose.

6. Tablets according to one or more of claims 1 to 5 wherein glucosamine hydrochloride and chondroitin sulphate are of fermentative origin.

7. Tablets according to one or more of claims 1 to 6 wherein Vitamin C is mi croencap sul ated .

8. Tablets according to one or more of claims 1 to 7 containing 250 mg of glucosamine hydrochloride, 200 mg of sodium chondroitin sulphate, 140 mg of L-ascorbic acid, 306.81 mg of sorbitol, 420 mg of xylitol, 0.42 mg of sucralose, 28 mg of magnesium stearate, flavors, and 14 mg of silica dioxide.

9. Tablets of claims 1-8 for use in the treatment and prevention of cartilage, tendon, and bone damage.

10. A process for preparing the tablets of claims 1-8 comprising: (a) fluid-bed granulation of a mixture consisting of the entire dose of Vitamin C, 90 to 95% of glucosamine, the entire dose of xylitol, and a portion of sorbitol comprised between 85 and 90% of its total weight expected in the final tablet, using an aqueous solution as an agglomerant wherein the remaining 5-10% of glucosamine is dissolved;

(b) drying of the obtained granulate and mixing in this order with

1. chondroitin sulphate,

2. the remaining sorbitol amount,

3. a sweetener,

4. anti-agglomerating agents,

5. flavors;

(c) pressing of the mixture obtained in (b).

11. A process for preparing chewable and/or suckable tablets comprising per unit dose 200 mg of sodium chondroitin sulphate, 250 mg of glucosamine hydrochloride, 140 mg of Vitamin C, characterized in that the excipients comprise sorbitol and xylitol in a weight ratio of 1 : 1.4 and in a concentration of 306.81 mg and 420 mg respectively, consisting of:

(a) fluid bed granulation of:

- Vitamin C;

- a sorbitol percentage between 85 and 90% of its total weight expected in the final tablet;

- xylitol;

- glucosamine in a percentage equal to 93% of the total weight expected in the final tablet; using a binding solution consisting of a solution of the remaining portion of glucosamine in a weight ratio glucosamine:water of 1 :4; 14

(b) drying and sieving;

(c) mixing of the obtained granules in this order with:

1. chondroitin sulphate;

2. a sweetener, preferably sucralose; 3. powdered flavors;

4. an anti-agglomerating agent, preferably silica dioxide;

5. flavors in a microencapsulated form;

6. the remaining percentage of sorbitol, between 10 and 15% of the total weight expected in the final tablet; (d) sieving and adding a second anti-agglomerating agent, preferably magnesium stearate;

(e) mixing and pressing of the mixture resulting from step (d).