SK121699A3 - Stable solid preparation containing vitamin d3 and tricalcium phosphate - Google Patents

Abstract

The invention relates to a stable solid preparation containing vitamin D3 and tricalcium phosphate in the treatment of osteoporosis and fractures of the femoral neck, vitamin D3 and/or calcium deficiencies as well as Paget's disease.

Description

The invention relates to a stable solid composition comprising vitamin D ₃ and tricalcium phosphate.

SUMMARY OF THE INVENTION

The pharmaceutical composition according to the invention consists of an active form of vitamin D ₃ and tricalcium phosphate and is free of organic solvent residues.

This novel composition has improved stability and can be used, for example, to prevent osteoporosis, to treat vitamin D ₃ and / or calcium deficiency, to prevent femoral neck fractures, and to prevent Paget's disease.

The invention further relates to a pharmaceutical composition comprising 100 to 1400 units of the active form of vitamin D ₃ and 1000 to 4500 mg of tricalcium phosphate. 1000 to 4500 tricalcium phosphate corresponds to 360 to 1640 mg of calcium. Preferably 200 to 1200 IU, in particular 400 to 1000 IU of the active form of vitamin D _{3 are used} . Further preferably, 1300 to 4000 mg of tricalcium phosphate, in particular 2600 to 3500 mg of tricalcium phosphate, are preferably used.

The invention further relates to a solid pharmaceutical composition, in the form of a powder or granules.

The invention further relates to a solid pharmaceutical composition, for once-daily oral administration, filled in sachets or in the form of tablets.

The invention further relates to a pharmaceutical composition in the form of a suspension prepared from powders before ingestion.

It is an object of the present invention to provide novel medicaments in the form of pharmaceutical compositions having better properties than known medicaments useful for the same purposes.

This object is solved by the invention of the novel composition. Surprisingly, it has been found that the active form of vitamin D ₃ can be formulated in combination with tricalcium phosphate.

Tricalcium phosphate has the formula Ca ₃ (PO ₄ ) ₂ ·

Particularly preferred active forms of vitamin D ₃ are those in which the active form has a hydroxyl group in the lapses, for example .alpha.-hydroxycholecalciferol, .alpha.-25-dihydroxycholecalciferol, .alpha.-24-dihydroxycholecalciferol, .alpha.-24,25-trihydroxycholecalciferol. -24-oxocholecalciferol, Ια, 25-dihydroxy-24-oxocholecalciferol, 1,1a, 25-dihydroxycholecalciferol 26,23-lactone, Ια, 25-dihydroxycholecalciferol-26,23-peroxylactone or 26,26,26,27,27,27,27,27,27,27,27,27,27,27 1a, 25-dihydroxycholecalciferol Further preferred are, for example, 25-hydroxycholecalciferol, 24-hydroxy cholecalciferol, 24-oxocholecalciferol, 24-25-dihydroxycholecalciferol, 25-hydroxy-24-oxocholecalciferol, 25-hydroxycholecalciferol-26,23 26,23-peroxylactone.

Particularly preferred is α-hydroxycholecalciferol, which is also called simply vitamin D ₃ or cholecalciferol.

EP 0 413828 and EP 0 702954 disclose pharmaceutical compositions comprising a combination of vitamin D ₃ and calcium salts. EP 0 413828 claims the preparation of active forms of vitamin D ₃ , including the active form of vitamin D ₃ , which is dispersed in an excipient readily soluble in an organic solvent and containing a basic substance. Tricalcium phosphate is not listed among the basic substances. The basic substance is used to stabilize vitamin D ₃ .

EP 0 702954 discloses a pharmaceutical composition comprising a calcium salt, vitamin D and at least one boron, copper or magnesium compound. A composition suitable for the treatment of osteoporosis may contain from 1000 to 2500 mg of calcium salt, corresponding to 400 to 1000 mg of calcium. Tricalcium phosphate as the calcium salt is not named. Said compounds of boron and copper can lead to undesirable side effects when used for a long time.

JP 05255095 discloses a composition comprising a microcrystalline calcium phosphate powder (hydroxylapatite or calcium triphosphate) and, for example, vitamin D ₃ . However, the invention is directed to iv administration and to vascular use.

As calcium source, additional calcium gluconate, calcium lactate, calcium citrate, dibasic calcium phosphate or preferably calcium carbonate are known to those skilled in the art and from the prior art.

Compared to the prior art, the composition according to the invention has surprising stability. The stability study data are shown in Table I by way of example of a single batch. In EP 0 413828, the results of the stability test are shown at p. 5 in Table I.

Surprisingly, in contrast to EP 0 413 828, the composition according to the invention can be produced without the use of organic solvents intended to dissolve sticky auxiliaries.

Compared to the 91% content of vitamin _D3, measured after 30 days at 40 ^e C and a relative humidity of 75% described in EP 0,413,828, p. 5, the composition according to the invention exhibits 97% vitamin D ₃ content under the same measurement conditions but after 13 weeks.

Table I

Stability of batch 41/95 produced according to example 2

Batch Appearance Contents No 41/95 scent taste of calcium- ferol [I.J.] Products degradation chole- kalci- Ferolit Contents waters [%] Contents Ca [g] Value PH Start corresponds 918 0.5% Tc 1.60 1.18 6.2 25 ^e C / 60% rel. humidity 13 weeks of responses 897 1.0% Ts. 1.64 1.19 6.2 26 weeks of responses 879 1.3% Tc. 0.9% Ts. 1.77 1.19 6.3 52 weeks of responses 849 1.2% Tc. 0.6% Ts. 1.45 1.19 6.2 30 * C / 60% 25 ^e C / 60% rel. humidity 26 weeks 861 1.5% Tc. 0.6% Ts. 1.77 1.18 6.2 52 weeks of responses 826 1.3% TC. 0.6% Ts. 1.41 1.19 6.2 40 ° C / 75% rel. humidity 13 weeks of responses 890 u.N 1.72 1.19 6.1 26 weeks of responses 757 0.6% Tc. 1.82 1.19 6.2

u.N .: below the Tc .: transcholecalciferol

Ts .: tachysterol I.J .: international unit

The process for the preparation of the pharmaceutical composition according to the invention consists in bringing the active form of vitamin D ₃ and tricalcium phosphate together with at least one solid carrier or excipient into a suitable dosage form by stirring.

The active form of vitamin D ₃ in the form of a solid concentrate is preferred. As the cholecalciferol concentrate, for example, Duphasol D3-1000 ^R dry stable or vitamin D3 type 100 CWS ^R is preferred.

Suitable carriers and excipients (binders and / or viscosity-increasing agents) are, for example, mannitol, hydroxypropylcellulose, lactose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, starch, crystalline cellulose, hydroxypropylmethylcellulose, ethylcellulose, carboxymethylcellulose, sorbitol, sorbitol, sorbitol, sorbitol, dextrin magnesium silicate), kaolin, precipitated calcium carbonate, sodium chloride, titanium dioxide, acacia and / or xanthan gum.

An aerosol is suitable, for example, as a flow aid.

Other carriers or excipients may be added, such as binders, antioxidants, colorants, emollients, sweeteners and / or flavorings. Suitable antioxidants are, for example, butylhydroxytoluol (BHT), propyl gallate, huty lhydroxyanisole (BHA), lecithin, α-tocopherol, hydroquinone, octyl gallate, dodecyl gallate, isoamyl gallate, nordihydroguialanic acid, guaiyl ester ester, α-naphthyrate ester, α-naphthytyl ester, α-naphthytyl ester ascorbic acid, cysteine hydrochloride, sodium ascorbic stearate, thioglycerol or thiosorbitol.

Suitable glidants or lubricants are, in particular, talc, starch, magnesium or calcium stearate, boric acid, paraffin, cocoa butter, macrogol, leucine or sodium benzoate.

As sweeteners, for example, aspartame or sodium saccharin are used, while flavoring agents are, for example, lemon or orange flavor.

As shown in Example 1, despite the high demands on uniformity of distribution of the active ingredients (see Example 2; 20 μ9 cholecalciferol in 4.1 g powder per bag), the preparation is characterized by simple mixing and without spray granulation, which is costly and as such is detrimental to stability.

The novel compositions of the invention may be prepared by bringing the active form of vitamin D ₃ and tricalcium phosphate together with a solid carrier or excipient into a suitable dosage form. The compositions thus obtained can be used as medicaments in both human and veterinary medicine, in particular for the prevention of osteoporosis and femoral neck fractures, also for the treatment of vitamin D ₃ and / or calcium deficiency states and for the prevention of Paget's disease. Suitable carriers are organic or inorganic substances which are suitable for oral administration and do not react with compounds selected from the group consisting of, for example, gelatin, soybean, carbohydrates such as lactose, mannitol or starch, magnesium stearate, talc and cellulose. For oral administration, in particular, tablets, dragees, capsules, suspensions or granules or powdered sachets are used in the form of suspensions.

The compositions may contain adjuvants such as preserving and stabilizing agents and / or wetting agents, emulsifying agents, coloring agents and / or flavoring agents.

The daily dose of vitamin D ₃ and tricalcium phosphate is preferably 200 to 1200 l of vitamin D ₃ and 1200 to 4000 mg of tricalcium phosphate, more preferably 400 to 1000 l of vitamin D ₃ and 1600 to 3500 mg of tricalcium phosphate and in particular 700 to 900 l of vitamin D

D ₃ and 3200 to 3500 mg of tricalcium phosphate. Oral administration is preferred.

Very preferred doses comprise 400 to 1000 µl of vitamin D ₃ and 1650 mg of tricalcium phosphate, or a double amount of 800 µl of vitamin D ₃ and 3300 mg of tricalcium phosphate, respectively.

The active ingredients of the novel pharmaceutical compositions are preferably administered in combination. However, they may be administered individually or sequentially.

The following examples relate to the manufacture and composition of the pharmaceutical compositions of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The cholecalciferol concentrate and sorbitol are sieved and mixed in the tumbler for 30 minutes (mixture a). Then, tricalcium phosphate, colloidal anhydrous silica, hydroxypropylmethylcellulose, gum arabic, gelatin, aspartame and lemon flavor are sieved and then the ingredients are mixed and blended in a drum blender for 30 minutes.

The mixture is sieved once more and then mixed again. The mixing of the components can also be carried out in a rapid mixer.

Example 2

The cholecalciferol-lactose concentrate is sieved and mixed in the tumbler for 30 minutes (mixture a).

Then tricalcium phosphate, colloidal anhydrous silica, hydroxypropylmethylcellulose, gum arabic, gelatin, aspartame and orange flavor are sieved, the ingredients are mixed with mixture a) and mixed in a drum blender for 30 minutes.

The mixture is sieved once more and then mixed again. The mixing of the components can also be carried out in a rapid mixer.

Example 3

The powder formulation filled into oral suspension bags containing 1.2 g of calcium and 20 μg of vitamin D ₃ has the following composition:

Cholecarcifenol concentrate * 8.0 mg sorbitol 227.0 mg tricalcium ** 3300,0 mg colloidal anhydrous silica 130.0 mg hydroxypropyl 150.0 mg arabic gum 175.0 mg saccharin sodium 10,0 mg natural lemon aroma 100.0 mg 4,100.0 mg

* corresponds to 800 IU cholecalciferol ** corresponds to 1.2 g calcium

Example 4

The powder formulation filled into oral suspension bags containing 0.6 g of calcium and 10 vitamin D ₃ has the following composition:

Cholecarcifenol concentrate * 4.0 mg sorbitol 114.0 mg tricalcium ** 1,650.0 mg colloidal anhydrous silica 65.0 mg

hydroxypropyl 75.0 mg xanthan resin 87.0 mg saccharin sodium 5.0 mg natural lemon aroma 50.0 mg

2050.0 mg * corresponds to 400 IU cholecalciferol ** corresponds to 0.6 g calcium

Example 5

The suspension, containing 1.2 g of calcium and 20 μg of vitamin D ₃ , has the following composition:

cholecarcifenol concentrate * ^** 8.0 mg sorbitol 227.0 mg tricalciumphosphate * * 3300,0 mg colloidal anhydrous silica 130.0 mg hydroxypropyl methylcellulose 150.0 mg arabic gum 175.0 mg saccharin sodium 10,0 mg natural lemon aroma 100.0 mg purified water 10,0 ml

* corresponds to 800 IU cholecalciferol ** corresponds to 1.2 g calcium

Industrial usability

Combination of vitamin D ₃ and tricalcium phosphate for the manufacture of pharmaceutical compositions for the prevention of osteoporosis, for the treatment of vitamin D ₃ and / or calcium deficiency, for the prevention of femur fractures and Paget's disease.

Claims (8)

A pharmaceutical composition comprising an active form of vitamin D ₃ and tricalcium phosphate without any organic solvent residues. 2. A pharmaceutical composition according to claim 1 comprising 100 to 1400 IU of active form of vitamin D ₃ and 1000 to 4500 mg of tricalcium phosphate. Pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of powder, tablets or granules. Pharmaceutical composition according to claims 1 to 3, characterized in that it is in a solid form for once-a-day oral administration and is filled in sachets or tablets. Pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a suspension which is prepared before ingestion from a powder. 6. A process for the production of a pharmaceutical composition which comprises the active form of a vitamin D ₃ and tricalcium phosphate together with at least one solid carrier or. the excipient, after mixing, to a suitable dosage form. Use of an active form of vitamin D ₃ and tricalcium phosphate for the manufacture of a medicament for the prevention of osteoporosis, and for the treatment of vitamin D ₃ and / or calcium deficiency conditions and for the prevention of Paget's disease. Use of a pharmaceutical composition comprising an active form of vitamin D ₃ and tricalcium phosphate for the treatment of diseases.