CN1823764A - Medicinal composition containing strontium fuminate and vitamin D - Google Patents

Abstract

The invention belongs to the field of pharmaceutical compound preparations, in particular to a pharmaceutical composition containing strontium ranelate (strontium ranelate) and vitamin D and a composite packaging composition thereof, comprising an effective therapeutic amount of strontium ranelate or a hydrate thereof , vitamin D and pharmaceutically acceptable auxiliary materials, wherein each single dose contains 0.5-3g of strontium ranelate and vitamin D100-1000IU. The composition of the present invention provides sufficient vitamin D nutritional supplement for postmenopausal women suffering from osteoporosis.

Description

A pharmaceutical composition containing strontium ranelate and vitamin D

technical field

The invention belongs to the field of pharmaceutical compound preparations, in particular to a pharmaceutical composition containing strontium ranelate and vitamin D and a composite packaging composition thereof. The present invention provides sufficient vitamin D nutritional supplements for postmenopausal women suffering from osteoporosis.

Background technique

Osteoporosis is a common disease that is easily overlooked by people. It is characterized by damage to the microstructure of bone tissue, a constant decrease in bone mineral composition and bone matrix, bone thinning, a decrease in the number of bone trabeculae, and bone fragility. A disease of systemic bone metabolism disorder that increases and increases the risk of fracture. Osteoporosis patients range from low back pain and limb weakness to hunched back and bone pain in severe cases. The direct harm is that the incidence of fractures is significantly increased. In particular, femoral neck fractures, vertebral fractures, and distal radius fractures that occur at the hip and wrist are known as the "three major fractures of osteoporosis." Because women's postmenopausal bone loss is significantly accelerated, women who have stopped menstruating for 15 to 20 years may lose 30% of their total body bone weight, so postmenopausal women are prone to postmenopausal osteoporosis. According to the report of the International Osteoporosis Foundation, there are 200 million women in the world suffering from osteoporosis, 1/3 of women aged 60-70 suffer from osteoporosis, and 2/3 of women over 80 years old suffer from osteoporosis. Can suffer one or more vertebral fractures accounted for 30%. Although the prevalence of osteoporosis in elderly men is lower than that of women of the same age group, once femoral neck fracture occurs in elderly men, the mortality rate is much higher than that of women.

Strontium ranelate (strontium ranelate), chemical name: 3-thiopheneacetic acid-5-[di(carboxymethyl)amino]-2-carboxy-4-cyano, strontium salt (1:2), structural formula see (I ). US Patent US5128367 (application date: 1990.08.37) discloses the structure, preparation method and application of strontium ranelate for treating osteoporosis. Developed by the French company Servier, it was approved for marketing in the UK in November 2004. It is the only osteoporosis drug with a dual mechanism of promoting bone formation and inhibiting bone resorption, and can effectively treat postmenopausal osteoporosis in women.

Molecular formula: C ₁₂ H ₆ N ₂ O ₈ SSr ₂ Molecular weight: 513.49

(I)

There are two important compounds of vitamin D, vitamin D2 and vitamin D3, which have no biological activity themselves, but they can generate biologically active calcitriol (1,25-(OH)2D3) after a series of catalysis in the body . Vitamin D can promote the absorption of calcium in the small intestine, and its metabolic active substances promote the reabsorption of phosphorus and calcium in the renal tubules, increase blood calcium and blood phosphorus concentrations, or maintain and regulate normal plasma calcium and phosphorus concentrations, and promote bone calcification. Therefore, when using estrogen antagonists and bisphosphonates to treat osteoporosis, vitamin D supplementation is required, and then their compound preparations or compound packaging products are developed, such as alendronate sodium and Vitamin D combination tablet. PCT patent application WO2006000224 discloses a compound preparation of strontium salts of strontium chloride, strontium carbonate, strontium maleate and other organic and inorganic acids and vitamins, but does not mention the compound preparation of strontium ranelate and vitamin D.

Similarly, when strontium ranelate treats osteoporosis in postmenopausal women, vitamin supplementation is also required. D.P.J.Emmanuel et al. (journal of endocrinol.metab.87:2026-2066, 2002) also clearly supplemented vitamin D and calcium in the process of evaluating the efficacy of strontium ranelate in the treatment of osteoporosis. In the instructions for use of strontium ranelate granules (Protelos) approved by the European Medicines Evaluation Agency (EMEA), it is disclosed that there is no drug interaction between strontium ranelate and vitamin D when administered simultaneously.

When strontium ranelate was used to treat osteoporosis in postmenopausal women, inhibition of bone resorption resulted in a slight decrease in blood calcium concentration, which was prominent in vitamin D insufficient patients. Vitamin D and calcium supplementation are therefore recommended during treatment with strontium ranelate. However, when taking strontium ranelate and taking vitamin D in addition, the taking method is more complicated and is easily forgotten by the patient, which brings great inconvenience to the patient and greatly reduces the compliance. Therefore, for the convenience of patients to take and improve compliance, it is necessary to provide patients with a pharmaceutical composition containing strontium ranelate and vitamin D, or to form a composite package of strontium ranelate and vitamin D. For this reason, the present invention People have completed the present invention through research.

Contents of the invention

The purpose of the present invention is to facilitate the patients who need to supplement vitamin D while taking strontium ranelate, and provide them with a pharmaceutical composition containing strontium ranelate and vitamin D.

The technical scheme that the present invention adopts is as follows:

A pharmaceutical composition containing strontium ranelate and vitamin D, the composition is a compound preparation comprising strontium ranelate or its hydrate, vitamin D and pharmaceutically acceptable excipients, or strontium ranelate or its hydrate Composite packaging of substance single-component preparations and vitamin D single-component preparations. The hydrate of strontium ranelate can be 4 hydrate, 7 hydrate, 8 hydrate, 9 hydrate.

The vitamin D in the pharmaceutical composition of the present invention may be vitamin D2 or vitamin D3. Among them, vitamin D3 is preferred.

The compound preparation composed of strontium ranelate or its hydrate, vitamin D and pharmaceutically acceptable auxiliary materials in the pharmaceutical composition of the present invention can be tablets, capsules, granules, chewable tablets, orally disintegrating tablets, oral solutions, Oral preparations such as syrups, suspensions, effervescent tablets, and powders. Granules, chewable tablets, tablets, capsules, suspensions, powders are preferred; granules and chewable tablets are more preferred.

The pharmaceutical composition of the present invention contains an effective therapeutic dose of strontium ranelate or hydrate 0.5-3g, preferably 1-2g, and contains vitamin D100-1000IU, preferably 400-800IU of vitamin D. Among them, strontium ranelate The content of strontium naphthalate hydrate is calculated by weight of strontium ranelate.

In addition to containing strontium ranelate and vitamin D, the pharmaceutical composition of the present invention also contains pharmaceutically acceptable auxiliary materials, such as fillers, disintegrating agents, flavoring agents, wetting agents or adhesives, lubricants or auxiliaries. Fluids, suspending agents, co-solvents or solubilizers, etc., can be combined arbitrarily according to the needs of different dosage forms. The filler can be selected from one or more of the following compounds: starch, pregelatinized starch, lactose, sugar, microcrystalline cellulose, mannitol and sorbitol, and the disintegrant can be selected from one or more of the following compounds Species: dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone, etc. Wetting agent and binder can be selected from one of the following compounds One or more kinds: water, ethanol, methylcellulose, sodium carboxymethylcellulose, povidone, hypromellose, hypromellose, etc., the lubricant is magnesium stearate, talcum powder or a mixture thereof , The flavoring agent can choose edible or medicinal essence, sucrose, sodium saccharin, aspartame, stevioside or a mixture thereof.

The pharmaceutical composition of the present invention is prepared according to the different preparation forms by adopting the conventional techniques of corresponding dosage forms. Such as granules, mix strontium ranelate and the above-mentioned suitable fillers of vitamin D, if necessary, add the above-mentioned suitable disintegrants or/and flavoring agents, and then add an appropriate amount of water or other binders to make a soft material , and then granulate, dry, sieve, and replace. For example, chewable tablets can be prepared according to conventional methods for tablet preparation.

The pharmaceutical composition of the present invention also relates to the composite packaging of strontium ranelate or its hydrate single-component preparation and vitamin D single-component preparation, wherein the strontium ranelate single-component preparation can be granules, chewable tablets or capsules, each A single dose contains strontium ranelate 0.5-2g; vitamin D single-component preparations can be capsules, soft capsules or tablets, each single dose contains vitamin D2 or D3 400-800IU, or alfacalcidol 0.5-1.0ug.

The above-mentioned composite packaging composition, wherein vitamin D can be vitamin D2, vitamin D3 or alfacalcidol, wherein, vitamin D2 is a capsule or tablet; vitamin D3 is a tablet; alfacalcidol is a tablet Agents and capsules, the specification is 0.5ug or 1.0ug.

The stability of the pharmaceutical composition of the present invention is tested according to the stability test method of the Chinese Pharmacopoeia, and the result proves that the composition of the present invention is stable, and strontium ranelate and vitamin D do not affect the stability of each other.

The pharmaceutical composition of the invention enables the patient to supplement the effective dose of vitamin D while taking the effective dose of strontium ranelate, which greatly facilitates the patient's medication. Vitamin D does not affect the bioavailability of strontium ranelate, on the contrary, it can effectively promote the absorption of calcium in the small intestine, and its metabolic active substances promote the reabsorption of phosphorus and calcium in the renal tubules, increasing blood calcium, blood phosphorus concentration, or Maintain and regulate the normal concentration of plasma calcium and phosphorus, promote bone calcification, benefit normal bone formation, and reduce the occurrence of potential complications caused by vitamin D deficiency, thus playing an active role in the treatment of postmenopausal women with osteoporosis.

The pharmaceutical composition of the present invention is used for treating postmenopausal women's osteoporosis.

Embodiment mode

The following examples serve to illustrate and further explain the invention but in no way limit it.

Embodiment 1——compound strontium ranelate vitamin D chewable tablet

Strontium ranelate 1000g

Vitamin D3 200,000 IU

Mannitol 500g

Aspartame 30g

10% Starch Slurry Appropriate amount

Sweet Orange Flavor 50g

Micropowder silica gel 10g

Made into 1000 pieces

The above prescription amounts of strontium ranelate, vitamin D3, mannitol and aspartame are uniformly mixed in equal amounts, and 10% starch slurry is made into a soft material, which is then granulated, dried, and granulated, and then mixed with essence and micro-powdered silica gel Evenly, and then pressed into pieces.

Application: the pharmaceutical composition obtained above is applied to treat postmenopausal osteoporosis and reduce the risk of vertebral and hip bone fractures. Chew orally, once a day, 2 tablets at a time, preferably two hours after eating and before going to bed.

Embodiment 2——compound strontium ranelate vitamin D granule

Strontium ranelate 2000g

Vitamin D3 800,000 IU

Mannitol 1200g

Dextrin 400

Aspartame 35g

Make 1000 bags

After mixing the raw and auxiliary materials in the above prescription amount evenly, granulate with water or 20% ethanol solution, dry the granules, granulate, then sieve into granules of appropriate size, and pack them into bags.

Application: the pharmaceutical composition obtained above is applied to treat postmenopausal osteoporosis and reduce the risk of vertebral and hip bone fractures. Take orally, once a day, 1 bag at a time, preferably two hours after eating and before going to bed. Stir each sachet with water before use, and then take it.

Example 3—Composite packaging of strontium ranelate single-component preparation and vitamin D single-component preparation

(1) Preparation of strontium ranelate chewable tablets

Strontium ranelate 1000g

Lactose 500g

Glycyrrhizin 30g

Sodium cyclamate 15

5% polyvinylpyrrolidone 50% ethanol solution Appropriate amount

Apple Flavor 50g

Talc powder 20g

Made into 1000 pieces

The above prescription amount strontium ranelate, lactose, glycyrrhizin and sodium cyclamate are mixed evenly, 5% polyvinylpyrrolidone 50% ethanol solution is made into a soft material, and then granulated, dried, granulated, and then mixed with apple essence and The talcum powder is mixed evenly, and then compressed into tablets.

(2) Preparation of strontium ranelate particles

Strontium ranelate 2000g

Mannitol 1200g

Dextrin 400

Aspartame 35g

Make 1000 bags

After mixing the raw and auxiliary materials in the above prescription amount evenly, granulate with water or 20% ethanol solution, dry the granules, granulate, then sieve into granules of appropriate size, and pack them into bags.

(3) Preparation of vitamin D capsules

Vitamin D2 or D3 400,000 IU

Vegetable oil Appropriate amount

Gelatin 100 parts

Glycerin 60 parts

Water 120 parts

Make 1000 capsules

Dissolve vitamin D2 or D3 with vegetable oil and adjust the concentration; mix glycerin and water in proportion and heat to about 70 degrees, stir and dissolve into gelatin; use liquid paraffin as cooling liquid to make pills, wash and dry.

(4) Preparation of Vitamin D Tablets

Vitamin D3 400,000 IU

Mannitol 40g

Microcrystalline Cellulose 25g

Sodium carboxymethylcellulose 10g

Povidone ethanol solution Appropriate amount

Micropowder silica gel 4g

Sodium Lauryl Sulfate 1g

Made into 1000 pieces

The above prescription amounts of vitamin D3, mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose are mixed uniformly in equal amounts, using povidone ethanol solution as a binder to make a soft material, which is granulated, dried and granulated Finally, micropowder silica gel and sodium lauryl sulfate are mixed, and then compressed into tablets.

(5) Preparation of vitamin D capsules

Vitamin D3 400,000 IU

Mannitol 80g

Microcrystalline Cellulose 40g

Sodium Carboxymethyl Cellulose 20g

Povidone ethanol solution Appropriate amount

Make 1000 capsules

The above prescription amounts of vitamin D3, mannitol, microcrystalline cellulose and sodium carboxymethyl cellulose are mixed uniformly in equal amounts, using povidone ethanol solution as a binder to make a soft material, which is granulated, dried and granulated Then pack into capsules.

(5) Composite packaging

According to (1) 14 tablets + (3) 7 tablets, (1) 14 tablets + (4) 7 tablets, (1) 14 tablets + (5) 7 tablets, (2) 7 bags + (3) 7 tablets, ( 2) 7 bags + (4) 7 tablets, (2) 7 bags + (5) 7 capsules are combined and packaged together to obtain a weekly dose of pharmaceutical composition, and the medicine containing 2g of strontium ranelate and 400IU of vitamin D is taken every day combination.

According to (1) 14 tablets + (3) 14 tablets, (1) 14 tablets + (4) 14 tablets, (1) 14 tablets + (5) 14 tablets, (2) 7 bags + (3) 14 tablets, ( 2) 7 bags + (4) 14 tablets, (2) 7 bags + (5) 14 tablets are combined and packaged together to obtain a weekly dose of pharmaceutical composition, and the medicine containing 2g of strontium ranelate and 800IU of vitamin D is taken daily combination.

Example 4: Stability study of strontium ranelate and vitamin D compound preparation

Taking the samples of Example 1 and Example 2 as examples, the stability study of the compound preparation of strontium ranelate and vitamin D was carried out.

After the sample was placed under the condition of high temperature 60°C and light for 5 days and 10 days, the properties of the sample, related substances and content uniformity did not change significantly.

After 6 months of accelerated test, the indicators of the sample did not change significantly.

The results showed that there was no interaction between strontium ranelate and vitamin D, and the quality of the compound preparation composed of the two was stable. At the same time, it has also been verified that the strontium ranelate granules described in the instructions have no interaction with vitamin D when taken at the same time.

Claims (10)

1. A pharmaceutical composition for treating or preventing osteoporosis, comprising an effective therapeutic dose of strontium ranelate or its hydrate, vitamin D and pharmaceutically acceptable excipients, wherein each single dose contains 0.5 strontium ranelate -3g, vitamin D100-1000IU. 2. The pharmaceutical composition of claim 1, wherein the content of said strontium ranelate per single dose is 1-2 g. 3. The pharmaceutical composition as claimed in claim 1, wherein the vitamin D content per single dose is 400-800 IU. 4. The pharmaceutical composition of claim 1, wherein said vitamin D is vitamin D2 or vitamin D3. 5. The pharmaceutical composition of claim 4, wherein said vitamin D is vitamin D3. 6. The pharmaceutical composition according to any one of claims 1-5, its preparation form can be tablet, capsule, granule, chewable tablet, suspension or powder. 7. The composition as claimed in claim 6, which is in the form of granules or chewable tablets. 8. A composite packaging composition for treating or preventing osteoporosis, which consists of strontium ranelate or its hydrate and vitamin D or its derivatives, characterized in that: strontium ranelate or its hydrate and vitamin D or Its derivatives are independent single-component preparations in the form of composite packaging, wherein, each single dose of strontium ranelate preparation contains 1-2 g of strontium ranelate; each single dose of vitamin D contains 400-800 IU of vitamin D. 9. The composite packaging composition as claimed in claim 8, wherein, said single-ingredient preparation, strontium ranelate or its hydrate is in the form of granules or chewable tablets, and vitamin D or its derivatives are in the form of capsules or tablets. 10. The composite packaging composition as claimed in claim 9, wherein said vitamin D is vitamin D2, vitamin D3 or α-calciferol.