MXPA00000684A - Pharmaceutical compositions containing vitamin d and calcium, their preparation and therapeutic use - Google Patents

Abstract

Described herein is a pharmaceutical composition containing Vitamin D and calcium, comprising a binding agent chosen from among the group consisting of:propylene glycol, a polyethylene glycol presenting a molecular weight comprised between 300 and 1500, liquid paraffin or silicone oil, useful for the treatment of nutritional deficiency of calcium and Vitamin D in the elderly.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING VITAMIN D AND CALCIUM, ITS PREPARATION AND THERAPEUTIC USE OF THE SAME Scope of the Invention The present invention relates to pharmaceutical compositions containing Vitamin D and a calcium salt, to the process for its preparation and to its use in the treatment of pathological forms that involve loss of bone tissue in the elderly, such as osteoporosis, as well as in the prevention of linked diseases such as calcium metabolism in the elderly, such as those that lead to fractures of the proximal femur or other non-vertebral fractures. STATE OF THE ART The use of Vitamin D and calcium salts, either separately or in association, for various diseases among which those that relate to calcium metabolism in the elderly, is already well documented in the state of The technique. For example, in FR 2724844, the existence of a therapeutic association is claimed between Vitamin D and calcium salts to combat osteoporosis. However, Vitamin D and currently available calcium-based pharmaceutical formulations still present a number of problems that do not totally acceptable. The problems that have had REF: 32466 im ^ i to face for the pharmaceutical compositions that are the subject of the present invention were in particular: a) the homogeneity of the distribution of Vitamin D3 in the final mixture; b) the flow properties of the calcium salt powder used; and when present, c) the speed of reconstitution of the suspension to be prepared as and when required. In fact, for the preparation of these formulations, Vitamin D is normally used in the so-called "coated" form, since it has greater stability than the pure crystalline form. The "coated" shape however has the disadvantage of consisting of small granules that are highly dense and smooth, which makes their distribution even more problematic within the final mix, this distribution in itself is already complex, considering that the small amount of the vitamin involved in comparison with the other constituents of the pharmaceutical compositions that are the subject matter of the present patent. In addition, the calcium salt used for this type of preparations is normally subjected to a granulation process (either wet or dry) to overcome the problems due to poor flow characteristics which it presents in its most widely used form, ie in the form of fine powder, which makes it unsuitable for processing using machines with high ordinary output speeds. However, the granules (including those obtained with specific excipients to promote disintegration) present a slow rate of disintegration, which on the contrary is highly convenient for the pharmaceutical preparation in bags, both in order to guarantee a good level of bio -availability, such as to obtain a suspension prepared as and when required, where the salt can be finely divided in order to reduce the sedimentation rate of the suspension and eliminate the "sand" effect that is noticed when taking granular suspensions of this type. Therefore there is an evident need for having new available pharmaceutical formulations containing an association of Vitamin D-calcium which can allow a high dosage of calcium in mixture in a homogeneous form with very low doses of Vitamin D (for example 1-2 g of calcium for 500-1000 IU of Vitamin D), can present a good stability, can have a high level of bio-availability, can be suitable to be processed using high-speed production machines and can be pleasant when taken by the patient.

Detailed Description of the Invention The pharmaceutical composition according to the invention makes it possible to overcome the aforementioned problems due to a "granulation" of the calcium salt, at the rate of 1-2 g of calcium for 500-1000 U.I. of Vitamin D, in the presence of propylene glycol or a polyethylene glycol having a molecular weight that is comprised between 300 and 1,500 (for formulations that involve subsequent disintegration in water) or in the case of pharmaceutical formulations that do not foresee subsequent disintegration) with liquid paraffin or silicone oil. Surprisingly, the addition of the calcium salt to the aforementioned glycols makes it possible to obtain a triple advantageous effect: a) The uniform and diffuse distribution of the glycol on the calcium granules, as well as on the other components of the formulation, plays a "binding" effect on the small granules of Vitamin D, coated. In this way, there is an anchoring of the particles of the vitamin to the system, thus allowing its uniform distribution; b) The atypical granulation of the calcium salt, which is carried out with this agent, modifies the flow properties enough to obtain a mixture which has characteristics of smoothness such as allowing its processing with high performance machines; c) The aforementioned modification of the flow properties of the calcium salt, however, is not an obstacle to its complete re-dispersion, when this is required once the aqueous suspension has been reconstituted. Furthermore, the humidifying effect exerted by propylene glycol on calcium phosphate should be considered. This effect makes the operation of reconstituting a dispersion, faster than that obtained without its use. According to the invention, propylene glycol is particularly preferred. In this connection it is important to note that the well known bitter taste of propylene glycol or some more bitter of polyethylene glycols of ba or molecular weight, can easily be covered by common excipients and sweeteners, without affecting the palatability of the resulting pharmaceutical composition. As binding agents for pharmaceutical forms that do not have to be dispersed in water, substances which have proven to be extremely useful and therefore constitute a subject of the present invention are liquid paraffin and silicone oil. These components make it possible to obtain the same effect of aggregation than the previous excipients and an equivalent distribution of the active ingredients. Among the various forms of Vitamin D used for the formulations according to the invention, Vitamin D3; Vitamin D2 and its mixtures are preferred. The calcium salt used for the present invention for example is selected from the group consisting of phosphate, glycero-phosphate, carbonate, bicarbonate, lactate, citrate, tartrate, gluconate and chloride. Particularly preferred is calcium phosphate and in particular tribasic phosphate. Typically, the amount of calcium phosphate is constituted between 30-80% by weight calculated based on the total composition. The pharmaceutical compositions forming the subject matter of the present patent still further comprise the usual wetting agents (for example sucrose palmitate); fluidifying agents (such as colloidal silica); suspending agents (such as cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose); organoleptic correctors (such as flavoring substances, citric acid); sweeteners (such as mannitol, sorbitol, saccharin salts, aspartame, etc.), - and coloring agents (such as E110). It should be noted that the pharmaceutical compositions according to the present invention are not suitable for dermatological applications (for example in the form of creams). According to a preferred formulation (bags) the pharmaceutical composition of the present application contains propylene or polyethylene glycol, in an amount comprised between 5-15% by weight calculated on the total weight of the formulation. Non-limiting examples of the present invention are the following: Example 1 Lot for 6000 bags. The palmitate of sucrose, citric acid and sodium saccharin are sifted using a sieve with 0.5-mm mesh. Propylene glycol is distributed over calcium phosphate in a high-speed granulator by adjusting the following process parameters: 2 minutes with impeller at 80 r.p.m. and the puller off, followed by 2 minutes with impeller at 160 rpm. and cutter at 1500 r.p.m. Colloidal silica, 25% of the required mannitol, citric acid and sodium saccharin are added to the mixture. The material is mixed for 6 minutes with the impeller 80 r.p.m. and cutter at 1500 r.p.m. until a homogeneous composition is obtained.

Prepared separately, in a bucket mixer at a speed of 25 r.p.m. for 15 minutes, this premix consists of sucrose palmitate, microcrystalline cellulose, and carboxymethyl cellulose, lemon flavor, E110, the remaining part of the hand and Vitamin D. The mixture thus obtained is transferred to the granulator and added with the rest of the preparation in accordance with the following parameters: 1 minute with impeller at 140 rpm and chopper at 1500 rpm., followed by 30 seconds with booster at 140 r.p.m and logger off. The granulate thus obtained is distributed in the bags, which thus contain a preparation having the following composition: tribasic calcium phosphate 3100 g (corresponding to 1200 mg of Ca "") Colcalciferol (Vit DA 100 000 Ul / g 0.008 g (corresponding to 800 IU) Propylene Glycol 0.800 g E110 0.002 g Colloidal silica 0.120 g Lemon flavor 0.100 g Microcrystalline cellulose -MCC 0.200 g Sodium saccharine 0.015 g Anhydrous citric acid 0.165 g Monopalmitate saccharof 0.120 g Mannitol is. at 7,000 g In a similar manner, but using polyethylene glycol instead of propylene glycol, bags containing a preparation with the following composition can be prepared: tribasic calcium phosphate 3100 g (corresponding to 1200 mg of Ca ") Colcalciferol (Vit D3) 100 000 IU / g 0.008 g (corresponding to 800 IU) Propylene Glycol 400 0.800 g E110 0.002 g Colloidal silica 0.120 g Lemon flavor 0.100 g Microcrystalline cellulose -MCC 0.200 g Sodium saccharine 0.015 g Anhydrous citric acid 0.165 g Sucrose monopalmitate 0.120 g Mannitol cs at 7,000 g Example 2 (tablets) Preparation for 20,000 tablets Liquid paraffin is distributed over calcium phosphate in a high-speed granulator, adjusting the following process parameters: 2 minutes with impeller at 80 r.p.m. and puller off, followed by 2 minutes with impeller at 160 r.p.m. and cutter at 1500 r.p.m. The colloidal silica, carboxy ethyl cellulose, sodium saccharin and orange sabopzante close together using a sieve with 0.5-mm mesh. Vitamin D3 is added to the aforementioned components and the product is mixed using a bucket mixer at a speed of 25 r.p.m. for 5 minutes. The sorbitol is then added, and everything is formulated in the bucket mixer for 10 minutes at 25 rpm This premix is transferred to the granulator and mixed with the rest of the preparation, adjusting the following process parameters: 1 minute with impeller at 140 rpm and shredder at 1500 rpm, followed by 30 seconds with impeller at 140 rpm and shredder off. The granulate is compressed to the weight required to obtain tablets having the following composition: Tribasic calcium phosphate 3.100 g (corresponding to 1200 mg of Ca ") Colcalciferol (Vit.D 100 000 IU / g 0.008 g (corresponding to 800 IU) Liquid parafilm 0.500 g Sodium carboxymethyl cellulose • 0.050 g Sodium saccharin 0.015 g Orange flavoring 0.100 g sorbitol es. at 4,400 g In the same way, using silicone oil instead of liquid paraffin, it is possible to obtain tablets having the following composition: Trisodium calcium phosphate 3,100 g (corresponding to 1200 mg of Ca ") Colcalciferol (Vit. D3) 100 000 IU / g 0.008 g (corresponding 800 IU) Silicone oil 0.500 g Sodium carboxymethyl cellulose 0.050 g Sodium saccharin 0.015 g Orange flavor 0.100 g Sorbitol cs at 4,400 g The pharmaceutical compositions forming the material of the present invention are developed for the purpose of being used in the treatment of nutritional deficiency of calcium and Vitamin D in the elderly, to reduce age-related loss of bone tissue and to prevent fractures of the proximal femur and other non-vertebral fractures. also used to prevent osteoporosis induced by chronic treatment with corticosteroids. U.I. as used in the present application means International Units and corresponds to the amount that has the activity 0.0025 and Vitamin D3. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Pharmaceutical composition containing as active ingredients Vitamin D associated with a calcium salt, characterized in that it comprises a binder selected from the group consisting of propylene glycol, a polyethylene glycol that has a molecular weight between 300 and 1500, liquid paraffin or silicone oil and that Vitamin D is present in the proportion of 1-2 g of calcium per 500 1000 IU of Vitamin D.
2. 2. Pharmaceutical composition according to claim 1, characterized in that the calcium used is in the form of a salt selected from the group consisting of phosphate, glophosphate, carbonate, bicarbonate, lactate, citrate, tartrate, gluconate and chloride .
3. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that the calcium salt is calcium phosphate.
4. 4. Pharmaceutical composition according to claim 3, characterized in that the calcium phosphate is 30-80% by weight calculated in the total composition.
5. 5. Pharmaceutical composition according to claim 1, characterized in that the Vitamin D used is Vitamin D2 (or ergocalciferol), Vitamin D, (or colcalciferol) or one of its mixtures.
6. 6. Pharmaceutical composition according to claim 1, characterized in that the vitamin used is Vitamin D3.
7. 7. A pharmaceutical composition (bag) according to claim 1, characterized in that it contains propylene glycol or polyethylene glycol in an amount comprised between 5-15% by weight calculated in a total composition.
8. 8. Pharmaceutical composition (tablet) according to claim 1, characterized in that it contains liquid paraffin or silicone oil.
9. 9. Pharmaceutical composition according to claim 1, characterized as follows: tribasic calcium phosphate 3100 g (corresponding to 1200 mg of CaA, Colcalciferol (Vit. D,) 100 000 IU / g 0.008 g (corresponding to 800 IU); Propylene glycol, 0.800 g, E110, 0.002 g, Colloidal silica, 0.120 g, Lemon flavor, 0.100 g, Microcrystalline cellulose - MCC, 0.200 g, Sodium saccharin, 0.015 g, Anhydrous citric acid, 0.165 g; Sucrose monopalmitate, 0.120 g; Mannitol c.s. at 7,000 g.
10. 10. Pharmaceutical composition according to claim 7, characterized as follows: tribasic calcium phosphate, 3100 g (corresponding to 1200 mg of Ca ++); Colcalciferol (Vit. D3) 100 000 IU / g, 0.008 g (corresponding to 800 IU); Propylene glycol 400, 0.800 g; Ell, 0.002 g; Colloidal silica, 0.120 g; Lemon flavor, 0.100 g; Microcrystalline cellulose -MCC, 0.200 g; Sodium saccharine, 0.015 g; Anhydrous citric acid, 0.165 g; Sucrose monopalmitate, 0.120 g; Mannitol, 7,000 g.
11. 11. Pharmaceutical composition according to claim 8, characterized as follows: Tribasic calcium phosphate, 3100 g (corresponding to 1200 mg of CaA, Colcalciferol (Vit. D;) 100 000 IU / g 0.008 g (corresponding to 800 IU) Liquid paraffin, 0.500 g, sodium carboxymethyl cellulose, 0.050 g, sodium saccharine, 0.015 g, orange flavoring, 0.100 g, sorbitol cs at 4.400 g,
12. 12. Pharmaceutical composition according to claim 8, characterized as follows: Tribasic calcium phosphate, 3100 g (corresponding to 1200 mg of Ca), Colcalciferol (Vit. D3) 100 000 IU / g 0.008 g (corresponding to 800 IU), Silicone oil, 0.500 g; * And i £ s? Sodium carboxymethyl cellulose, 0.050 g; Sodium saccharine, 0.015 g; Orange flavors, 0.100 g; Sorbitol c.s. at 4,400 g.
13. 13. Process for the preparation of a pharmaceutical composition according to claims 1 and 7, characterized by the following steps: a) in a granulator that rotates at high speed, distribute the binder, consisting of propylene glycol or polyethylene glycols of low molecular weight on calcium salt; b) add the colloidal silica, approximately 25% of the mannitol, citric acid and sodium saccharin and mix for the required time and at the appropriate speed; c) add the mixture, prepared separately, consisting of saccharine palmitate, a suspension agent, flavoring agent, coloring agent, the remaining part of the hand and Vitamin D, and mix with the rest of the preparation; d) distribute the granulate thus obtained in bags.
14. 14. Process for the preparation of a pharmaceutical composition according to claims 1 and 8, characterized in that the following steps: a) in a granulator that rotates at high speed, distribute the binder, consisting of liquid paraffin or silicone oil on calcium salt; b) add in order, to a mixture of colloidal silica, carboxymethyl cellulose and previously sifted sodium saccharin, Vitamin D3 and sorbitol, mix thoroughly each time before a new ingredient is added, empty the mixture in the rotary granulator and mix by the time required and at the appropriate speed; c) compressing the granulate to the weight required to obtain the desired tablets.
15. 15. Composition according to claim 1, for use in the treatment of nutritional deficiency of calcium and vitamin D in the elderly, to reduce bone loss associated with age and to prevent femoral fractures, and other nb vertebral fractures. refers to a pharmaceutical composition containing vitamin D and calcium, comprising a binder selected from the group consisting of propylene glycol, a polyethylene glycol having a molecular weight between 300 and 1500, liquid paraffin or silicone oil, useful in the treatment of calcium and vitamin D nutptional deficiency in the elderly.