CN103142642B - Calcitriol and calcium carbonate suspension granule and preparation method thereof - Google Patents

Abstract

The invention relates to a calcitriol and calcium carbonate suspension granule and a preparation method thereof. The suspension granule is prepared from the following ingredients in percentage by weight: 0.0005% of calcitriol, 5-10% of calcium carbonate, 2.0-4.0% of meglumine, 1.2-1.8% of polyethylene glycol 400, 12-18% of polyethylene glycol 6000, 45-75% of filler, 5.0-10.0% of disintegrant and an appropriate amount of binder. According to the suspension granule, the content of calcitriol is remarkably increased, so that the drug dosage is reduced; and the stability of calcitriol to light and air is improved, and the bioavailability of calcitriol is also remarkably improved.

Description

Mix suspension grain of calcitriol and calcium carbonate and preparation method thereof

Technical field

The present invention relates to pharmaceutical technology field, be specifically related to mix suspension grain of a kind of calcitriol and calcium carbonate and preparation method thereof.

Background technology

Calcitriol (Calcitriol) is white crystalline powder, to light and air-sensitive.Be slightly soluble in methanol, ethanol, ethyl acetate.Tm is 111-115 ℃.It is one of most important metabolic activity product of vitamin D3 in human body, has the intestinal absorption of impelling calcium and regulates in sclerotin the effects such as inorganic salt transhipment; Be mainly used in osteoporosis; The renal osteodystrophy of Patients with Chronic Renal Failure, particularly needs the patient of chronic hemodialysis; After operation, spontaneity and false parathyroid gland machine go down; Vitamin D3 dependency rickets and hypophosphatemia vitamin D resistance rickets; The dermatosiss such as psoriasis; And other vitamin D deficiencies.The oral absorption of calcitriol is fast, within 3～6 hours, reaches peak, t1/2 approximately 3～6 hours, and after 7 hours, urinating calcium concentration increases, the sustainable pharmacologically active of single oral dose 3～5 days.Strontium Ranelate, as a kind of new compound, has anti-bone resorption and promotes bone formation dual function, can be used in treatment osteoporosis.The osteoporosis that calcitriol and Strontium Ranelate administering drug combinations be can be used for treating to various former or secondary.

Calcium carbonate is the best of being widely used raw material of replenishing the calcium, its calcium content is high, cheap, good absorbing in body, but comparatively common with chewable tablet on the market, although there is the advantage of its preparation itself, also obviously there is defect in some place, such as the poor children taking of masticatory ability, child is in eugonic period, and current domestic child's great majority all need to replenish the calcium, and chewable tablet is obviously not suitable for children taking.

When calcitriol and calcium carbonate are made to compositions and share, because calcitriol is to light and air-sensitive, said composition exists the content of effective ingredient calcitriol extremely low, the problem that bioavailability is low.

Summary of the invention

Research worker is surprisingly found, while preparing the mix suspension grain of calcitriol and calcium carbonate, the meglumine adding in right amount, PEG400 and polyethylene glycol 6000, can significantly improve content, stability and the bioavailability of calcitriol in preparation, thereby can reduce the consumption of calcium carbonate, so there is unforeseeable technique effect, significant for the clinical use of medicine.

The invention provides a kind of active component content is high, medicine stability good, bioavailability is high calcitriol and the mix suspension grain of calcium carbonate.This mix suspension grain is made by the component of following percentage by weight:

Calcitriol 0.0005%

Calcium carbonate 5-10%

Meglumine 2.0-4.0%

PEG400 1.2-1.8%

Polyethylene glycol 6000 12-18%

Filler 45-75%

Disintegrating agent 5.0-10.0%

Binding agent is appropriate.

Its optimizing prescriptions is:

Calcitriol 0.0005%

Calcium carbonate 8.0%

Meglumine 3.0%

PEG400 1.5%

Polyethylene glycol 6000 15%

Filler 60%

Disintegrating agent 8.0%

Binding agent is appropriate.

Further, above-mentioned filler is selected from one or more in starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.

Further, above-mentioned disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and sodium alginate.

Further, above-mentioned binding agent is selected from one or more in starch, pregelatinized Starch, hyprolose, hypromellose and polyvidone.

The preparation method of this mix suspension grain is:

1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve standby;

2) binding agent of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4), after granulating with 40 mesh sieves, dry 30-60min at 50-70 ℃, crosses 20 mesh sieve granulate; After No. 4 sieve sieves, remove fine powder, subpackage, sealing, packing and get final product.

The preparation method of this mix suspension grain is more preferably:

1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves standby;

2) binding agent of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4) after granulating with 40 mesh sieves, dry 45min at 60 ℃, crosses 20 mesh sieve granulate, after No. 4 sieve sieves, removes fine powder, subpackage, sealing, packing and get final product.

The invention has the beneficial effects as follows:

1. in said preparation, the content of calcitriol significantly increases, and has reduced the dose of medicine;

2. improved the stability of calcitriol to light, air having added of meglumine, PEG400 and polyethylene glycol 6000, its bioavailability is also significantly improved, thereby has reduced the consumption of calcium carbonate in compositions.

The specific embodiment

Below in conjunction with concrete embodiment, technical scheme of the present invention is further described.

The mix suspension grain of embodiment 1 calcitriol and calcium carbonate

Prescription is:

Calcitriol 1.5mg

Calcium carbonate 15g

Meglumine 6.0g

PEG400 3.6g

Polyethylene glycol 6000 36g

Starch 210g

Carboxymethyl starch sodium 15g

Pregelatinized Starch is appropriate.

Preparation method is:

1) take the supplementary material of recipe quantity, cross respectively 80 mesh sieves standby;

2) pregelatinized Starch of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, starch and carboxymethyl starch sodium by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4) after granulating with 40 mesh sieves, dry 30min at 50 ℃, crosses 20 mesh sieve granulate, after No. 4 sieve sieves, removes fine powder, subpackage, sealing, packing and get final product.

The mix suspension grain of embodiment 2 calcitriols and calcium carbonate

Prescription is:

Calcitriol 1.5mg

Calcium carbonate 30g

Meglumine 12g

PEG400 5.4g

Polyethylene glycol 6000 54g

Lactose 150g

Low-substituted hydroxypropyl cellulose 30g

Hyprolose is appropriate.

Preparation method is:

1) take the supplementary material of recipe quantity, cross respectively 120 mesh sieves standby;

2) hyprolose of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, lactose and low-substituted hydroxypropyl cellulose by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4) after granulating with 40 mesh sieves, dry 60min at 70 ℃, crosses 20 mesh sieve granulate, after No. 4 sieve sieves, removes fine powder, subpackage, sealing, packing and get final product.

The mix suspension grain of embodiment 3 calcitriols and calcium carbonate

Prescription is:

Calcitriol 1.5mg

Calcium carbonate 24g

Meglumine 9.0g

PEG400 4.5g

Polyethylene glycol 6000 45g

Dextrin 180g

Microcrystalline Cellulose 24.0g

Polyvidone is appropriate.

Preparation method is:

1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves standby;

2) polyvidone of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, dextrin and microcrystalline Cellulose by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4) after granulating with 40 mesh sieves, dry 45min at 60 ℃, crosses 20 mesh sieve granulate, after No. 4 sieve sieves, removes fine powder, subpackage, sealing, packing and get final product.

The mix suspension grain of comparing embodiment 1 calcitriol and calcium carbonate

Calcitriol 1.5mg

Calcium carbonate 24g

PEG400 4.5g

Polyethylene glycol 6000 45g

Dextrin 180g

Microcrystalline Cellulose 24.0g

Polyvidone is appropriate.

Preparation method is same embodiment 3:

The mix suspension grain of comparing embodiment 2 calcitriols and calcium carbonate

Calcitriol 1.5mg

Calcium carbonate 24g

Meglumine 9.0g

Polyethylene glycol 6000 45g

Dextrin 180g

Microcrystalline Cellulose 24.0g

Polyvidone is appropriate.

Preparation method is with embodiment 3.

The mix suspension grain of comparing embodiment 3 calcitriols and calcium carbonate

Calcitriol 1.5mg

Calcium carbonate 24g

Meglumine 9.0g

PEG400 4.5g

Dextrin 180g

Microcrystalline Cellulose 24.0g

Polyvidone is appropriate.

Preparation method is with embodiment 3.

Embodiment 4 stability experiments and result

1. accelerated stability test

Intensity of illumination 4500lx, adopted HPLC method to carry out assay in the 0th, 5 and 10 days after timing sampling.

The condition of HPLC is: chromatographic column: ODS-C18 post, take octadecylsilane chemically bonded silica as filler; Mobile phase: acetonitrile-water (75:25); Detect wavelength: 265nm; Flow velocity: 1.0mL/min; Sample size: 50 μ L.Theoretical cam curve is pressed the calculating of calcitriol peak should be not low by 5000, and calcitriol peak and the peak-to-peak separating degree of trans calcitriol should be greater than 1.0.Adopt external standard method to calculate content.Assay result (percentage ratio of the amount of recording and labelled amount) sees the following form 1.Result shows that the stability of active component calcitriol in the mix suspension grain of calcitriol of the present invention and calcium carbonate is obviously better than comparative example.

Table 1 accelerated stability test assay result (%)

2. long-term stable experiment

25 ℃ of temperature, relative humidity are placed 36 months for 60% time, respectively at 0,3,6,12,24 and 36 months time sampling adopt HPLC method to carry out assay.The same accelerated stability test of condition of HPLC.Adopt external standard method to calculate content.Assay result (percentage ratio of the amount of recording and labelled amount) sees the following form 2.Result shows that the stability of active component calcitriol in the mix suspension grain of calcitriol of the present invention and calcium carbonate is obviously better than comparative example.

Table 2 long-term stable experiment assay result (%)

The comparative test of embodiment 5 bioavailability

4 beasle dogs (being male) are carried out to oral administration, they are fed respectively with the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3 calcitriol and the mix suspension grain of calcium carbonate (25 ℃ of temperature, relative humidity are placed 12 months for 60% time), dosage is 5.0 μ g/ only (in calcitriol), and be 7 days the interval time of each administration.Give after medicine, blood sample collection under different time, and carry out the maximum haemoconcentration (C of calcitriol _max) and bioavailability (AUC _{0 → 48}) calculating.Acquisition time is 0h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 32h, 48h.

Following table 3 provides the average result that 4 beasle dogs is given to the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example's 3 calcitriol and the mix suspension grain gained of calcium carbonate.As seen from table, the maximum haemoconcentration of the calcitriol of the mix suspension grain of calcitriol of the present invention and calcium carbonate (embodiment 3) and bioavailability are apparently higher than comparative example.

The comparison of table 3 bioavailability (5.0 μ g, n=3)

Should be noted that; the foregoing is only preferred embodiment of the present invention; be not limited to scope of the present invention, every any modification of having done within the spirit and principles in the present invention, the replacement being equal to and improvement etc., within all should being included in protection scope of the present invention.

Claims (7)

1. a mix suspension grain for calcitriol and calcium carbonate, is characterized in that, by the component of following percentage by weight, is made:

2. the mix suspension grain of calcitriol according to claim 1 and calcium carbonate, is characterized in that, by the component of following percentage by weight, is made:

3. the mix suspension grain of calcitriol according to claim 1 and 2 and calcium carbonate, is characterized in that, described filler is selected from one or more in starch, lactose, dextrin and Icing Sugar.

4. the mix suspension grain of calcitriol according to claim 1 and 2 and calcium carbonate, it is characterized in that, described disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and sodium alginate.

5. the mix suspension grain of calcitriol according to claim 1 and 2 and calcium carbonate, is characterized in that, described binding agent is selected from one or more in starch, hyprolose, hypromellose and polyvidone.

6. the preparation method of the mix suspension grain of the calcitriol described in claim 1-5 any one and calcium carbonate, is characterized in that, the method comprises the steps:

1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve standby;

2) binding agent of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4), after granulating with 40 mesh sieves, dry 30-60min at 50-70 ℃, crosses 20 mesh sieve granulate; After No. 4 sieve sieves, remove fine powder, subpackage, sealing, packing and get final product.

7. the preparation method of the mix suspension grain of calcitriol claimed in claim 6 and calcium carbonate, is characterized in that, the method comprises the steps:

1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves standby;

2) binding agent of getting after sieving adds distilled water, makes binder solution;

3) by the calcitriol after sieving, calcium carbonate, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;

4) after granulating with 40 mesh sieves, dry 45min at 60 ℃, crosses 20 mesh sieve granulate, after No. 4 sieve sieves, removes fine powder, subpackage, sealing, packing and get final product.