MXPA06009804A

MXPA06009804A - Pharmaceutical compositions comprising bisphosphonates and vitamins weekly and fortnightly administered

Info

Publication number: MXPA06009804A
Application number: MXPA/A/2006/009804A
Authority: MX
Inventors: Guillermo Alvarez Ochoa Victor; Santos Murillo Josefina; Elena Garcia Armenta Maria
Original assignee: Worldtrade Importexport Wtie Ag*
Filing date: 2006-08-29
Publication date: 2008-09-02

Abstract

The present invention refers to the combination of monosodic ibandronate and D3 vitamin, and to the manufacturing process thereof, the invention having an improved bioavailability for the weekly or fortnightly administration thereof to patients suffering from osteoporosis. ?? ?? ?? ??

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING BISPHOS- FONATES AND VITAMINS FOR WEEKLY ADMINISTRATION AND BIWEEKLY FIELD OF THE INVENTION The present invention is related to the pharmaceutical industry in general and to the pharmaceutical industry that prepares drugs for the treatment of osteoporosis with a better bioavailability in particular. More specifically, the present invention relates to a pharmaceutical composition for oral administration, consisting of a combination of bisphosphonates or physiologically acceptable salts thereof and vitamins preferably D3, as well as the process for the preparation of these combinations in a single unit of dose.

BACKGROUND Bone loss begins to occur more rapidly in women at menopause. This change in bone density persists with age contributing to osteoporosis and an increased risk of fractures in elderly women. Among the factors most commonly identified and most studied that induce osteoporosis are estrogen deficiency in women in the menopause stage and deficiencies in calcium and vitamin D3.

The consequence of bone degradation is an increased risk of vertebral fractures or in other sites in post-menopausal women and in vertebral or femoral sites in the elderly. It has been shown that the prevalence of calcium and vitamin D insufficiency increases in the elderly population. The intake of calcium and vitamin D is effective in reducing the loss of bone mass, decreasing the incidence of fractures.

Among the bisphosphonates, ibandronate is one of the most powerful inhibitors of osteoclast activity. It reduces the loss of bone minerals and does not produce qualitative alterations in the mineralization. It has been shown that with the use of bisphosphonates there is a 50% reduction in the incidence of vertebral and femoral fractures in subjects with pre-existing fractures.

The problem of bisphosphonates is their reduced bioavailability due to their physico-chemical characteristics, for this reason the objective of these studies was the development of a product combined with Ibandronate and vitamin D3, which would offer an improved bioavailability so that it would have a better therapeutic effect and with a weekly and / or biweekly administration.

DETAILED DESCRIPTION OF THE INVENTION Bisphosphonates are substances used in the treatment of bone diseases and some disorders of bone metabolism such as osteoporosis and Paget's disease.

Most of the bisphosphonates that are currently marketed are found in oral pharmaceutical forms (capsules and tablets) and intravenous injectable forms.

However, due to the physicochemical characteristics of bisphosphonates, they have a poor bioavailability, causing gastrointestinal adverse events, with the consequent therapeutic detachment.

On the other hand, its poor bioavailability makes it difficult to combine them with other substances, especially vitamins such as D3 that would further affect the bioavailability of bisphosphonates.

For this reason and before this problem we develop a process that can combine these two substances producing a synergistic effect, with an improvement of bioavailability, a weekly or biweekly administration that reduces the risk of adverse gastrointestinal events, which produces a greater therapeutic effect as well as a greater attachment to treatment by the patient.

We have reviewed that the stability of this combination is increased by adding excipients such as crospovidone during the granulation stage together with the active substances and also adding a part of lactose material. These compositions dissolve more easily, having greater stability during storage in relation to temperature and humidity.

The pharmaceutical composition according to the invention comprises Ibandronate monosodium equivalent to 17.5 mg of Ibandronate and 2,800 IU of Vitamin D3 in addition to Ibandronate monosodium equivalent to 37.5 mg of Ibandronate and 6,000 IU of Vitamin D3.

The composition further comprises adjuvants such as cellulose, lactose, polyvinylpyrrolidone, Povidone, re-ticked polyvinyl pyrrolidone, cross carmellose, stearic acid, magnesium stearate, colloidal silicon dioxide.

The dosage units are coated tablets. According to the inventions, the core of the tablet consists of 19 to 22% of the active substances, 6.5 to 8% by weight of polyvinylpyrrolidone, 50 to 65% by weight of lactose, 6 to 7.5% by weight of crospovidone, 2 to 4% colloidal silicon dioxide.

The polyvinylpyrrolidone is added to the granulate together with the active substances and with a part of the lactose.

Process: By wet granulation of Ibandronate or pharmaceutically acceptable salt thereof and vitamin D3 together with adjuvants such as polyvinylpyrrolidone and a portion of lactose; the polyvinylpyrrolidone is added to the granulation mixture.

Subsequently, the wet granulate is dried, and when dry is screened, the other adjuvants such as lactose, stearic acid and colloidal silicon dioxide are added and mixed before processing.

The active substances, a part of lactose and the cross-linked polyvinylpyrrolidone in the form of a dry powder are granulated by spraying an aqueous polyvinylpyrrolidone solution into the powder mixture.

The process is carried out at a temperature of 70 ° C. The atomized granulated material is dried after a temperature of 70 ° C and sieved through a fine sieve; the dried granulate is mixed with the remaining amount of lactose, stearic acid and silicon dioxide that have previously passed through a fine sieve.

The final mixture is pressed into cores of tablets which are coated with the coating suspension using purified water and a film coating mixture by dissolving the polyvinylpyrrolidone in purified water, charging the fluidized bed dryer with the active ingredients apart from the lactose monohydrate and up to 60% by weight of cellulose and the cross-linked polyvinylpyrrolidone; granulating by atomized the active principles at a temperature of 70 ° C and then, screening the dry intermediate through a fine sieve.

Mixing the dry granulate with the remaining amount of cellulose, stearic acid and colloidal silicon that previously passed through the fine sieve.

Compressing the final mixture (granulate) in tablet cores and coating the tablet with a coating suspension using purified water and a film coating mixture with hypromellose, titanium dioxide, talc and macrogol 6000.

Example 1: The preparation of a tablet coated with a film, containing 17.5 mg of the active substance (Ibandronate sodium) and vitamin D3 2,800 IU; It is carried out as follows: 1. Povidone K25 is dissolved in purified water. 2. A fluid bed dryer is loaded with the nosodonic salt of ibandronic acid, vitamin D3, lactose monohydrate, crospovidone and microcrystalline cellulose. The crospovidone and the microcrystalline cellulose were passed through a fine sieve before mixing. 3. The materials of stage 2 are granulated by atomization at 70 ° C with the granulation fluid from stage 1. 4. A final drying of the atomized granulate material from stage 3 is carried out at 70 ° C. 5. Screening the dry granulated intermediate through a fine sieve (2 mm perforations) and 6. When necessary, repeat steps 1-5 to obtain the final lot size. 7. The granulate from step 6 is mixed in a mixing vessel with microcrystalline cellulose, stearic acid and anhydrous colloidal silica. The microcrystalline cellulose, the stearic acid and the anhydrous colloidal silicon were passed through a fine sieve (1 mm) before mixing. 8. Combine the final mixture of step 7 in tablet cores using a rotary tablet press. 9. The coating suspension is prepared using purified water, film coating mixture comprising hypromellose, titanium dioxide and talc (Macrogol 6000). 10. The coating suspension of step 9 is atomized onto the tablet cores using a coating unit.

The composition of the tablet is as follows: Tablet core Ibandronic acid 17.5 mg As a monosodium salt of Ibandronic acid 30.0 mg Vitamin D3 0.7 mg Povidone K25 10 mg Lactose monohydrate 80 mg Microcrystalline cellulose 15 mg Crospovidone 10.0 mg Stearic acid 95 5.0 mg Anhydrous colloidal silica 4.5 mg Film coating Film coating mixture 4.0 mg Macrogol 6000 2.0 mg The weight of the core is 142.7 mg and the total weight of the tablet is 148.7 mg., The amount of active substances per tablet is equivalent to 17.5 mg of free ibandronic acid and 0.7 mg of Vitamin D3.

Example 2: The preparation of a tablet coated with a film containing 37.5 mg of Ibandronate sodium and vitamin D3 1.5 mg was carried out as described in example 1 Tablet core Ibandronic acid 37.5 mg As monosodium salt of Ibandronic acid 56.0 mg Vitamin D3 1.5 mg Povidone 15.0 mg Lactose monohydrate 100 mg. Microcrystalline cellulose 20 mg Crospovidone 12.0 mg Stearic acid 95 6.0 mg Anhydrous colloidal silica 5.0 mg Film coating Film coating mixture 6.0 mg Macrogol 6000 3.0 mg The weight of the core of the tablet is 197 mg and the total weight of the tablet is 206 mg, the amount of active substances per tablet is equivalent to 37.5 mg of free ibandronic acid and 1.5 mg of Vitamin D3,

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, what is contained in the following claims is related as property: R E I V I N D I C A C I O N S

1. A pharmaceutical composition characterized in that it contains as an active substance Ibandronate monosodium 17.5 mg and vitamin D3 2,800 IU and monosodium Ibandronate 37.5 mg and vitamin D3 6,000 IU in a single dose unit.

2. A pharmaceutical composition according to claim 1, characterized in that the core of the tablet consists of: 21 to 22% active substances. 6.5 to 7.5% by weight of binder. 55 to 57% by weight filler. - 7 to 7.5% by weight of disintegrant. 3 to 4% by weight of lubricant 3 to 4% by weight of flow regulator.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the core of the tablet consists of: 19 to 20% active substances. 7 to 8% by weight of binder. 50 to 65% by weight of filler. - 6 to 7% by weight of disintegrant. 3 to 4% by weight of lubricant. 2 to 3% by weight of flow regulator.

4. A pharmaceutical composition according to any of claims 1 to 3 characterized in that it comprises the equivalent of 17.5 mg of monosodium Ibandronate and 4,800 IU (0.7 mg) of Vitamin D3.

5. A pharmaceutical composition according to any of claims 1 to 4, characterized in that it comprises the equivalent of 37.5 mg of monosodium Ibandronate and 6,000 Ul (1.5 mg) of Vitamin D3.

A pharmaceutical composition characterized in that it contains: Ibandronic acid 17.5 mg As a monosodium salt of Ibandronic acid 30.0 mg. Vitamin D3 0.7 mg Povidone K25 10 mg Lactose monohydrate 80 mg Microcrystalline cellulose 15 mg Crospovidone 10.0 mg Stearic acid 95 5.0 mg Colloidal silica anhydrous 4.5 mg Film coating Film coating mixture 4.0 mg Macrogol 6000 2.0 mg

7. A pharmaceutical composition characterized in that it contains: Ibandronic acid 37.5 mg As monosodium salt of Ibandronic acid 56.0 mg Vitamin D3 1.5 mg Povidone 15.0 mg Lactose monohydrate 100 mg. Microcrystalline cellulose 20 mg Crospovidone 12.0 mg Stearic acid 95 6.0 mg Anhydrous colloidal silica 5.0 mg Film coating Mixture of film coating 6.0 mg Macrogol 6000 3.0 mg

8. A pharmaceutical composition according to claims 1, 2, 3, 4, 5, 6 and 7 characterized in that the disintegrant is added to the granulate together with the active substances and with a part of the lactose.

9. A process for the preparation of a composition according to claims 1 to 8, characterized in that the process comprises: a) Granulating the monosodium Ibandronate, a part of the lactose and the crospovidone with a solution of the povidone in purified water to a temperature of 70 ° C. b) Dry the granulated material at a temperature of 70 ° C and then screen the dry intermediate through a fine sieve. c) Mix the granulate with the remaining amount of lactose, stearic acid and colloidal silicon dioxide that was previously passed through a fine sieve. d) Compress the final mixture in tablet core and coat the tablet with a coating suspension using purified water and a coating film mixture.

10. A process according to claim 9, characterized in that the process comprises: a) Dissolving the povidone in purified water; b) Charge a dryer with monosodium Ibandronate and vitamin D3, a portion of lactose and povidone; c) Granulating the material from stage b) at a temperature of 70 ° C with the granulation fluid of stage a); d) Dry the granulated atomized material of step c) at a temperature of 70 ° C and then screen the intermediate dried through a fine sieve; e) Mixing the granulate of step d) in a mixer with the remaining amount of lactose, stearic acid and colloidal silicon dioxide which has previously passed through a fine sieve; f) Compressing the final mixture of e) in tablet cores and coating the tablet with a film coating suspension;

11. A pharmaceutical composition characterized in that the combination of these active ingredients and the process result in a tablet in a single dose unit for the weekly and fortnightly treatment of Osteoporosis, with an improved bioavailability.