CN101444521B - Pharmaceutical preparation containing alendronate sodium and cholecalciferol-cholesterol - Google Patents
Pharmaceutical preparation containing alendronate sodium and cholecalciferol-cholesterol Download PDFInfo
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- CN101444521B CN101444521B CN200710170980XA CN200710170980A CN101444521B CN 101444521 B CN101444521 B CN 101444521B CN 200710170980X A CN200710170980X A CN 200710170980XA CN 200710170980 A CN200710170980 A CN 200710170980A CN 101444521 B CN101444521 B CN 101444521B
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Abstract
The invention provides a pharmaceutical composition which contains alendronate sodium, cholecalciferol-cholesterol, antioxidizer and a pharmaceutically acceptable carrier. The invention also provides the usage of the pharmaceutical composition in treating osteoporosis.
Description
Invention field
The present invention relates to a kind of osteoporotic pharmaceutical preparation that is used to treat, be specifically related to comprise the pharmaceutical preparation of Alendronate sodium and cholecalciferol-cholesterol.
Background technology
Osteoporosis " Primary Care " at present commonly used clinically reach " the powerful treatment ", is exactly according in various degree osteoporotic and different phase, the different therapeutic scheme of working out according to the difference of individuality.
Primary Care generally refers to vitamin D and treats.According to diet and living habit, the absorption of people's calcium every day and vitamin D is insufficient often, especially the old people.Even take in competent calcium nutrition, if but the Deficiency of Intake of vitamin D has often also limited the abundant absorption of calcium.
The general recommendation of the intake of vitamin D every day is 400-1000IU." Primary Care " both can prevent the generation of osteoporosis, can also effectively prevent and treat bone loss and corresponding fracture risk due to the SHPT.In general, " Primary Care " be safety relatively, and the generation of side effect is seldom arranged, but its effect that improves bone density, reduction fracture incidence rate is not still affirmed.
" powerful treatment " generally refers to bis phosphoric acid salt (like Alendronate sodium) and treats.It is generally acknowledged that these medicines can effectively improve bone density, improve the symptom of osteoporosis quickly, and can effectively reduce fracture rates.
Owing to also have many mistaken ideas in the osteoporosis treatment, for example some people thinks that " powerful treatment " just needn't treat at use vitamin D class medicine.But, having only " powerful treatment " and " Primary Care " when combining, could play a role better.For example, clinical " therapy " of generally acknowledging is the application of vitamin D+periodic Diphosphonate, and this merges pain for senile osteoporosis, and significantly the patient is especially effective.
In a word, " Primary Care " associating " powerful treatment " is exactly that income is reached 1+1＞2, just drops to side effects of pharmaceutical drugs minimumly, can bring up to comparatively ideal degree to the effect of treating again.
Alendronate sodium is a kind of Diphosphonate, and it is the re-absorbed specific inhibitor of bone that osteoporosis is regulated.Diphosphonate is a kind of that in bone, find and bonded synthetic of hydroxyapatite.
The structural formula of Alendronate sodium:
Molecular formula: C
4H
12NNaO
7P
23H
2O
Molecular weight: 325.12
Zooscopy finds that Alendronate sodium has the following action mode.At cellular level, Alendronate sodium particularly has close preferendum in the position of osteoclast effect to the bone resorption position.Under the normal condition, osteoclast adheres to bone surface but the edge is not coarse, and rough edge then is the active sign of bone resorption.Alendronate sodium does not influence the gathering or the adhesion of osteoclast, but it can suppress the activity of osteoclast really.The associated mark that carries out in the mice body has the research of radioactivity (3H) Alendronate sodium site of action in bone to show, the absorption on osteoclast surface is 10 times of osteoblast surface.(3H) Alendronate sodium that is marked with radioactivity gives rat respectively after 6 days and 49 days, checks that its osseous tissue finds that normal bone is formed at above the Alendronate sodium, the latter with no longer have pharmacologically active after substrate combines.Therefore, Alendronate sodium must continue to take to suppress the osteoclast of the new sorbent surface that forms.The tissue morphology measurement of baboon and rat learns and shows, Alendronate sodium can reduce bone conversion (that is, bone is rebuild the quantity at position), and rebuilds the position at these, and bone formation surpasses bone resorption, thereby the bone amount is increased gradually.
Cholecalciferol-cholesterol be vitamin D3 and cholesterol etc. the crystallization that is compounded to form of mole, it has the effect of regulating calcium, phosphorus metabolism and formation skeleton, can promote the absorption of calcium simultaneously.Vitamin D3 is the necessary element of normal bone formation.The structural formula of cholecalciferol-cholesterol:
Molecular formula: C
54H
90O
2
Molecular weight: 771.3
Vitamin D3 produces through ultraviolet radiation at skin.The photochemical reaction that irradiation produces becomes 7-dehydrogenation cholecalciferol the precursor of vitamin D3.Change into vitamin D3 through non-enzyme isomerization then.When lacking suitable solar radiation, vitamin D3 can only absorb from food.Vitamin D3 in the skin and the vitamin D3 in the food (absorb and get into Chylomicron) are converted into 25-hydroxyvitamin D3 (being calcifediol) at liver; It is converted into the hormone 1 of active calcium-circulation, 25-dihydroxy vitamin d3 (calcitriol) through parathryoid hormone and hypophosphatemic stimulation at kidney again.1, the main effect of 25-dihydroxy vitamin d3 is to increase calcium ion and phosphatic intestinal absorption, regulates blood calcium, kidney calcium and phosphatic elimination simultaneously, and enhance bone forms and bone heavily absorbs.
Vitamin D is the necessary element of normal bone formation.When illumination deficiency and food intake deficiency, all can cause vitamin D deficiency.The D that is deficient in vitamin can cause passive calcium balance, and the parathryoid hormone level increases, and osteoporosis also increases the risk of fracturing.Serious vitamin D deficiency can cause more serious parathryoid hormone level, hypophosphatemia, decline of nearside muscle and osteoporosis.
The folk prescription product that has only Alendronate sodium and cholecalciferol-cholesterol in the market.For example: alendronic Acid sodium tablet (trade name FOSAMAX; Merck company); Cholecalciferol-cholesterol slice (Chongqing Kerui Pharmaceutical Co) and milk of cholecalciferol-cholesterol (attending friendship Jin Zhu pharmaceutcal corporation, Ltd of Hisense); The rachitic control of D property that is used to be deficient in vitamin of cholecalciferol-cholesterol slice and milk of cholecalciferol-cholesterol, wherein milk of cholecalciferol-cholesterol mainly to as if infant.Report milk of cholecalciferol-cholesterol treatment senile osteoporosis patient's preliminary observation of curative effect (Chinese osteoporosis magazine, the 3rd the 1st phase of volume of February in 1997,53-54 page or leaf) is also arranged, certain effect is arranged though the result shows the milk of cholecalciferol-cholesterol of folk prescription, but undesirable.2005; The compound tablet of alendronate sodium vitamin D 3 (trade name FOSAMAXPLUS D, Merck company) is by FDA approval listing, and it treats the Alendronate sodium sheet that osteoporotic curative effect is superior to folk prescription; Because when preventing that bone runs off, additional vitamin D3 can promote the absorption of calcium.But the vitamin D3 raw material is unstable, has caused a lot of inconvenience except giving to produce to store, and peroral dosage form has been caused restriction, and the vitamin D3 product through national SFDA approval has only the injection dosage form at present, does not have other dosage form.
The compound product of cholecalciferol-cholesterol and Alendronate sodium is not disclosed in the prior art.
Therefore, for solving the deficiency of existing product, this patent will provide a kind of pharmaceutical composition and various dosage form thereof, and said composition has significant curative effect for the treatment osteoporosis.
Summary of the invention
Inventor of the present invention finds, unites and uses Alendronate sodium and cholecalciferol-cholesterol to have good especially curative effect for the treatment osteoporosis.
One aspect of the present invention provides a kind of pharmaceutical composition, and it comprises Alendronate sodium, cholecalciferol-cholesterol, antioxidant and pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, said antioxidant is selected from cresol, tertiary butyl-4-hydroxy methoxybenzene, vitamins antioxidant such as vitamin C or E, sodium pyrosulfite, L-cysteine hydrochloride, gallic acid second fat and EDTA-2Na.
In a preferred embodiment of the present invention, said pharmaceutically acceptable carrier is selected from filler, disintegrating agent, fluidizer, lubricant, binding agent and solvent.
In a preferred embodiment of the present invention, the consumption of said Alendronate sodium is the 5-100 weight portion, is preferably the 10-90 weight portion, is the 10-80 weight portion better, is preferably the 10-70 weight portion.
In a preferred embodiment of the present invention, the consumption of said cholecalciferol-cholesterol is the 0.1-0.5 weight portion, is preferably the 0.11-0.4 weight portion, is the 0.12-0.3 weight portion better, is preferably the 0.14-0.28 weight portion.
In a preferred embodiment of the present invention, the consumption of said antioxidant is the 0.1-20 weight portion, is preferably the 0.1-15 weight portion, is the 0.2-12 weight portion better, is preferably the 0.3-10 weight portion.
In a preferred embodiment of the present invention, said pharmaceutical composition also comprises solubilizing agent.
In a preferred embodiment of the present invention, the consumption of said solubilizing agent is the 1-2000 weight portion, is preferably the 2-1800 weight portion, is the 3-1700 weight portion better, is preferably the 5-1550 weight portion.
In a preferred embodiment of the present invention, the dosage form of said pharmaceutical composition is granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture, suspension or solution.
The present invention provides the purposes of said pharmaceutical composition in the treatment osteoporosis on the other hand.
The present invention forms compound recipe with Alendronate sodium and cholecalciferol-cholesterol first, cholecalciferol-cholesterol be vitamin D3 and cholesterol etc. the mole conjugate, its raw material cholecalciferol-cholesterol be vitamin D3 and cholesterol etc. the crystallization that is compounded to form of mole; Its bioavailability and stability are superior to vitamin D3; For producing and the preservation condition of providing convenience, through adding antioxidant, more improved stability simultaneously; Be fit to process various peroral dosage forms, the middle-aged and elderly people osteoporosis that treatment is on the rise.
The specific embodiment
One aspect of the present invention provides a kind of pharmaceutical composition, and it comprises Alendronate sodium, cholecalciferol-cholesterol, antioxidant and pharmaceutically acceptable carrier.
In the present invention, said Alendronate sodium is conventional.Usually, said Alendronate sodium can be any type of product, for example can be form and other conventionally form of hydrate.In an instance of the present invention, said Alendronate sodium is the commercially available prod, for example available from the three water alendronic Acid list sodium salts of Shan Xi Han Jiang Pharmacy Co. Ltd.
In the present invention, the consumption of said Alendronate sodium is conventional, and those of ordinary skill in the art can know directly that which consumption can be used among the present invention.In a preferred embodiment of the present invention, the consumption of said Alendronate sodium is the 5-100 weight portion, is preferably the 10-90 weight portion, is the 10-80 weight portion better, is preferably the 10-70 weight portion.
In the present invention, said cholecalciferol-cholesterol is conventional.Usually, said cholecalciferol-cholesterol can be any type of product, for example pressed powder, emulsion form and other conventionally form.In an instance of the present invention, said cholecalciferol-cholesterol is the commercially available prod, for example available from the cholecalciferol-cholesterol of Chongqing Kerui Pharmaceutical Co.
In the present invention, the consumption of said cholecalciferol-cholesterol is conventional, and those of ordinary skill in the art can know directly that which consumption can be used among the present invention.In a preferred embodiment of the present invention, the consumption of said cholecalciferol-cholesterol is the 0.1-0.5 weight portion, is preferably the 0.11-0.4 weight portion, is the 0.12-0.3 weight portion better, is preferably the 0.14-0.28 weight portion.
In the present invention, the amount ratio of said Alendronate sodium and cholecalciferol-cholesterol is conventional, and those of ordinary skill in the art can select suitable weight ratio arbitrarily according to the two amount ranges.In a preferred embodiment of the present invention, the weight ratio of said Alendronate sodium and cholecalciferol-cholesterol is 100-1000, is preferably 150-750, is 200-650 better, is preferably 250-500.
In the present invention, said antioxidant is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which antioxidant can be used for the present invention.In a preferred embodiment of the present invention, said antioxidant is selected from cresol, B.H.A (tertiary butyl-4-hydroxy methoxybenzene), vitamins antioxidant such as vitamin C or E, sodium pyrosulfite (Na
2S
2O
5), L-cysteine hydrochloride (L-Cys hydrochlorate), gallic acid second fat (C
9H
10O
5), EDTA-2Na etc.
In the present invention, the consumption of said antioxidant is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said antioxidant according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption of said antioxidant is the 0.1-20 weight portion, is preferably the 0.1-15 weight portion, is the 0.2-12 weight portion better, is preferably the 0.3-10 weight portion.
In the gross weight of said pharmaceutical composition, the content of said antioxidant is generally 0.01-1 weight %, is preferably 0.05-0.8 weight %, better is 0.08-0.6 weight %, is preferably 0.1-0.3 weight %.
In the present invention, said solubilizing agent is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which solubilizing agent can be used for the present invention.In a preferred embodiment of the present invention, said solubilizing agent is selected from non-ionic surface active agent (like tween 80, Arlacel-85), castor oil hydrogenated and gelatin.
In the present invention, the consumption of said solubilizing agent is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said solubilizing agent according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption of said solubilizing agent is the 1-2000 weight portion, is preferably the 2-1800 weight portion, is the 3-1700 weight portion better, is preferably the 5-1550 weight portion.
In the gross weight of said pharmaceutical composition, the content of said solubilizing agent is generally 1-10 weight %, is preferably 1.5-9 weight %, better is 2-8 weight %, is preferably 3-7.5 weight %.
In the present invention, said pharmaceutically acceptable carrier is conventional, and those of ordinary skill in the art can know directly that which pharmaceutically acceptable carrier can be used among the present invention.Usually, said pharmaceutically acceptable carrier comprises filler, disintegrating agent, fluidizer, lubricant, binding agent, solvent or the like.
In the present invention, the consumption of said carrier is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said carrier according to the general knowledge of this area.In a preferred embodiment of the present invention, in the weight in the said pharmaceutical composition, the consumption of said pharmaceutically acceptable carrier is 30-99 weight %, is preferably 35-97 weight %, better is 40-95 weight %, is preferably 54%-90 weight %.
In the present invention, said filler is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which filler can be used for the present invention.In a preferred embodiment of the present invention, said filler is selected from lactose, microcrystalline Cellulose, starch, amylum pregelatinisatum, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, mannitol and sorbitol.
In the present invention, the consumption of said filler is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said filler according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption of said filler is the 40-200 weight portion, is preferably the 50-180 weight portion, is the 60-150 weight portion better, is preferably 80-130 weight %.
In the gross weight of said pharmaceutical composition, the consumption of said filler is generally 20-80 weight %, is preferably 25-75 weight %, better is 28-65 weight %, is preferably 30-60 weight %.
In the present invention, said disintegrating agent is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which disintegrating agent can be used for the present invention.In a preferred embodiment of the present invention, said disintegrating agent is selected from croscarmellose sodium, crospolyvinylpyrrolidone, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose etc.
In the present invention, the consumption of said disintegrating agent is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said disintegrating agent according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption 1-50 weight portion of said disintegrating agent is preferably the 2-40 weight portion, is the 4-30 weight portion better, is preferably the 6-20 weight portion.
In the gross weight of said pharmaceutical composition, the consumption of said disintegrating agent is generally 1-10 weight %, is preferably 1.5-9 weight %, better is 2-8 weight %, is preferably 3%-7.5 weight %.
In the present invention, said fluidizer is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which fluidizer can be used for the present invention.In a preferred embodiment of the present invention, said fluidizer is selected from colloidal silica.
In the present invention, the consumption of said fluidizer is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said fluidizer according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption 0.1-1 weight portion of said fluidizer is preferably the 0.2-0.9 weight portion, is the 0.3-0.8 weight portion better, is preferably the 0.4-0.6 weight portion.
In the gross weight of said pharmaceutical composition, the consumption of said fluidizer is generally 0.05-1 weight %, is preferably 0.1-0.8 weight %, better is 0.15-0.7 weight %, is preferably 0.2%-0.5 weight %.
In the present invention, said lubricant is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which lubricant can be used for the present invention.In a preferred embodiment of the present invention, said lubricant is selected from magnesium stearate and Pulvis Talci.
In the present invention, the consumption of said lubricant is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said lubricant according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption 0.1-1 weight portion of said lubricant is preferably the 0.15-0.9 weight portion, is the 0.2-0.8 weight portion better, is preferably the 0.2-0.6 weight portion.
In the gross weight of said pharmaceutical composition, the consumption of said lubricant is generally 0.1-10 weight %, is preferably 0.2-8 weight %, better is 0.4-6 weight %, is preferably 0.5-5 weight %.
In the present invention, said binding agent is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which binding agent can be used for the present invention.In a preferred embodiment of the present invention, said binding agent is selected from ethanol water, starch slurry, hypromellose, Polyethylene Glycol, sucrose solution, methylcellulose, hyprolose of water, polyvinylpyrrolidone (PVP K30) solution, dehydrated alcohol or different weight percentage etc.
In the present invention, said adhesive consumption is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said binding agent according to general knowledge of the present invention.In a preferred embodiment of the present invention, said adhesive consumption 0.1-50 weight portion is preferably the 0.5-30 weight portion, is the 0.8-20 weight portion better, is preferably the 1-10 weight portion.
In the gross weight of said pharmaceutical composition, said adhesive consumption is generally 0.5-10 weight %, is preferably 1-8 weight %, is the 1.5-6 weight portion better, is preferably 2-4.5 weight %.
In the present invention, said solvent is conventional, and those of ordinary skill in the art can know directly that according to general knowledge of the present invention which solvent can be used for the present invention.In a preferred embodiment of the present invention, said solvent is selected from water, Oleum Camelliae and polyethylene glycol 6000 (PEG 6000).
In the present invention, the consumption of said solvent is conventional, and those of ordinary skill in the art can directly obtain the concrete consumption of said solvent according to general knowledge of the present invention.In a preferred embodiment of the present invention, the consumption 80-99.9 weight % of said solvent is preferably 85-99 weight %, better is 90-95 weight %.
Usually; Pharmaceutical composition of the present invention is the form oral administration as follows: tablet, capsule, dispersible powder, granule or suspension (containing 0.05-5% suspending agent according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing the 20-50% ethanol of having an appointment), perhaps carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspending agent of having an appointment in the medium waiting to ooze).
Common pharmaceutical dosage form comprises the oral or non-oral administration of the form of granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture, suspension, solution.
For oral administration, can use tablet (ordinary tablet, dispersible tablet, oral cavity disintegration tablet), capsule (soft capsule, hard capsule), drop pill, granule (powder), Emulsion or solution.
For parenteral administration, can use injection and infusion solution.
See that from the position that is easy to prepare preferred pharmaceutical composition is a solid-state composition, especially the capsule of filling of tablet and solid or liquid filling with administration.Oral administration is preferred.
Embodiment
Embodiment 1: Alendronate sodium cholecalciferol-cholesterol ordinary tablet or capsule
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3)
With Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Microcrystalline Cellulose (pH301) | 30mg | Japan company of Asahi Chemical Industry |
| Lactis Anhydrous | 43mg | New Zealand lactose company |
| Croscarmellose sodium | 15mg | Anhui Shanhe Medical Accessary Material Co., Ltd. |
| Sucrose | 10mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Colloidal silica | 0.5mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Magnesium stearate | 0.2mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gelatin | 25mg | Qinghai gelatin limited company |
| Cresol | 0.3mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Modified food starch | 10mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gross weight | 225.51mg or 225.65mg |
The tablet method for making:
(1) 0.14g cholecalciferol-cholesterol and 25g gelatin, 0.3g cresol heating for dissolving are cooled off, crushing screening obtains mixture of powders then.In the gained mixture of powders, add 43g Lactis Anhydrous, 30g microcrystalline Cellulose and 10g sucrose with the equivalent method of progressively increasing, then the mix homogeneously thing that is uniformly mixed.
(2) in step (1) gained mixture, add 91.37g three water alendronic Acid list sodium salts, 15g croscarmellose sodium and 0.5g colloidal silica, mix homogeneously is crossed 60 mesh sieves then and is got mixture of powders.
(3) with 50% starch slurry step (2) gained mixture is processed soft material, cross 30 mesh sieves; Dry back adds 0.2g magnesium stearate mix homogeneously.
(4) step (3) gained mixture is carried out the stamping of 9mm scrobicula, get 1000 tablets.
The capsule method for making:
First three step is the same.
(4), get 1000 capsules with step (3) gained mixture filled capsules.
Embodiment 2: Alendronate sodium cholecalciferol-cholesterol Orally taken emulsion
Specification: 10ml: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and 10ml: Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every bottle of consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Oleum Camelliae | 0.75g | Zhejiang Long Youxian gathers emerging grain and oil medication chemistry company limited |
| Tween 80 | 0.6g | The Zhejiang dragon emerging grain and oil medication chemistry company limited of getting together for fun |
| Arlacel-85 | 0.15g | Shen, Shanghai space medication chemistry company limited |
| B.H.A (tert-butyl group-4-BHA) | 0.01g | Shen, Shanghai space medication chemistry company limited |
| Sodium benzoate | 0.03g | Hunan Er-kang Pharmaceutical Co., Ltd. |
| Water for injection | Add to 10ml |
Method for making:
(1) tween 80, Arlacel-85 and Oleum Camelliae are heated to 100 ℃ and carry out sterilization treatment, take by weighing the 600g tween 80 after the cooling, 150g Arlacel-85 and 750g Oleum Camelliae place container, are mixed into oil phase.
(2) 0.14g cholecalciferol-cholesterol and 10gBHA are progressively added in the oil phase in the stirring, be heated to 55 ℃ of constant temperature simultaneously, be stirred to it and dissolve back one-tenth oil phase A fully.
(3) 91.37g three water alendronic Acid list sodium salts and 30g sodium benzoate are dissolved into aqueous phase B with 30% water for injection.
(4) in oil phase A, once add an amount of aqueous phase B, form mixture; The gained mixture is processed the colostrum of W/O shape under 4000-5000 rev/min mixing speed in homogenizer; Continue to stir colostrum, progressively adding aqueous phase B simultaneously, to make it phase inversion be O/W type Emulsion, adds the injection water to 10000ml.
(5) step (4) gained Emulsion is carried out the secondary homogenize, fills nitrogen, fill 10ml/ bottle, the Orally taken emulsion of the even emulsion of milky.
Embodiment 3: Alendronate sodium cholecalciferol-cholesterol drop pill
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every bottle of consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| The L-cysteine hydrochloride | 0.25mg | Shanghai aginomoto company limited |
| PEG6000 | 900mg | Gao Nan chemical plant, PVG |
Method for making:
(1) gets 900gPEG 6000 oil baths and be heated to 135 ℃, in PEG6000, add 0.14g cholecalciferol-cholesterol, 91.37g three water alendronic Acid list sodium salts and 0.3g L-cysteine hydrochloride then, stir simultaneously and make whole dissolvings, filtered while hot; Filtrating is placed liquid containing bottle, in 135 ℃ of insulations.
(2) dropper that is respectively 9.0mm and 9.8mm with external diameter in the mouth of pipe splashes in step (1) gained filtrating in simethicone (outer the is ice-water bath) liquid coolant, and this filtrating is condensed into ball.
(3) ball of step (2) gained is washed ball, promptly get Alendronate sodium cholecalciferol-cholesterol drop pill.
Embodiment 4: Alendronate sodium cholecalciferol-cholesterol soft capsule
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Vitamin E | 2mg | Zhejiang Medicine Co |
| Oleum Camelliae | 750mg | Zhejiang Long Youxian gathers emerging grain and oil medication chemistry company limited |
Method for making:
(1) the 0.14g cholecalciferol-cholesterol is added the dissolving of 750g Oleum Camelliae, add 91.37g three water Alendronate sodium list sodium salts then, mix homogeneously gets solution.
(2) step (2) gained solution is prepared soft capsule with the rotating mould platen press.
Embodiment 5: Alendronate sodium cholecalciferol-cholesterol micropill (encapsulated)
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Microcrystalline Cellulose (pH301) | 30mg | Japan company of Asahi Chemical Industry |
| Lactis Anhydrous | 43mg | New Zealand lactose company |
| Croscarmellose sodium | 15mg | Anhui Shanhe Medical Accessary Material Co., Ltd. |
| Sucrose | 10mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gelatin | 5mg | Qinghai gelatin limited company |
| Cresol | 0.3mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Modified food starch | 5.5mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gross weight | 200.31mg or 200.45mg |
Method for making:
(1) the 0.14g cholecalciferol-cholesterol is dissolved in the 5g gelatin solution of heating, adds 0.3g cresol then, stirring and dissolving.
(2) in step (1) gained solution, add the 55g10% farinaceous size again, stir.
(3) with 91.37g three water alendronic Acid list sodium salts and 43g Lactis Anhydrous, 30g microcrystalline Cellulose, 10g sucrose and 15g croscarmellose sodium with the equivalent method mix homogeneously that progressively increases.
(4) step (3) gained mixture is added in step (2) the gained starch slurry, be made into soft material then; The gained soft material is extruded particle and round as a ball with the extrusion granulator spheronizator.
(5) with step (4) gained particle cold drying (vacuum drying oven or boiling drier), promptly get micropill.
(6) with the fill of step (5) gained micropill to capsule.
Embodiment 6: Alendronate sodium cholecalciferol-cholesterol dispersible tablet
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Microcrystalline Cellulose (pH301) | 48mg | Japan company of Asahi Chemical Industry |
| Lactis Anhydrous | 80mg | New Zealand lactose company |
| Carboxymethyl starch sodium (CMS-Na) | 12.5mg | Anhui Shanhe Medical Accessary Material Co., Ltd. |
| Crospolyvinylpyrrolidone (PVPP) | 7.5mg | Germany BASF AG |
| Sodium lauryl sulphate (SLS) | 2mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Polyvinylpyrrolidone (PVP K30) | 1.0mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Magnesium stearate | 0.25mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gross weight | 242.76mg or 242.9mg |
Method for making:
(1) with 0.14g cholecalciferol-cholesterol, (2g) SLS and (80g) Lactis Anhydrous mix homogeneously, grinds and carry out micronization.
(2) in step (1) gained powder, add 91.37g three water alendronic Acid list sodium salts, 48g microcrystalline Cellulose, 6.25gCMS-Na and 7.5gPVPP, mix homogeneously with the equivalent method of progressively increasing.
(3) use 20g5%PVP K30 serosity that step (2) gained mixture is processed soft material, cross 24 mesh sieves, dry then.
(4) in the dry soft material of step (3) gained, add 6.25gCMS-Na and 7.5gPVPP, mix homogeneously.
(5) in step (4) gained mixture, add 0.25g magnesium stearate, mix homogeneously.
(6) make step (5) gained material carry out the stamping of 9mm scrobicula, promptly get dispersible tablet.
Embodiment 7: Alendronate sodium cholecalciferol-cholesterol powder
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3)
With Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Microcrystalline Cellulose (pH301) | 30mg | Japan company of Asahi Chemical Industry |
| Lactis Anhydrous | 43mg | New Zealand lactose company |
| Croscarmellose sodium | 15mg | Anhui Shanhe Medical Accessary Material Co., Ltd. |
| Sucrose | 10mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gelatin | 5mg | Qinghai gelatin limited company |
| Cresol | 0.3mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| 30 POVIDONE K 30 BP/USP 30 | 5.5mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Simethicone | 0.2mg | Guangdong U.S. mark adjuvant company |
| Hypromellose | 2mg | The happy Kanggong of Shanghai card department |
| The Rhizoma et radix valerianae cream flavour | 1mg | The precious essence company limited of Shanghai China |
| Gross weight | 201.51mg or 201.65mg |
Method for making:
(1) the 0.14g cholecalciferol-cholesterol is dissolved in the 5g gelatin solution of heating, in gained solution, adds 0.3g cresol, stirring and dissolving.
(2) in step (1) gained solution, add 55g10% 30 POVIDONE K 30 BP/USP 30 serosity, stir.
(3) with 91.37g three water alendronic Acid list sodium salts and 43g Lactis Anhydrous, 30g microcrystalline Cellulose, 10g sucrose and 15g croscarmellose sodium and 1g Rhizoma et radix valerianae cream flavour with the equivalent method mix homogeneously that progressively increases.
(4) in step (2) gained 30 POVIDONE K 30 BP/USP 30 serosity, add step (3) gained mixture, make and process soft material, extrude particle and round as a ball with the extrusion granulator spheronizator then.
(5) with step (4) gained particle cold drying (vacuum drying oven or boiling drier), use 3% hypromellose solution coating then, make weightening finish 1%, obtain the coating powder.
(6) step (5) gained coating powder is packaged in the good pouch of sealing.
Embodiment 8: Alendronate sodium cholecalciferol-cholesterol oral cavity disintegration tablet
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3) and Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Microcrystalline Cellulose (pH302) | 56.5mg | Japan company of Asahi Chemical Industry |
| Lactis Anhydrous | 40mg | The world special article company |
| Crospolyvinylpyrrolidone (PVP-XL) | 6mg | Anhui Shanhe Medical Accessary Material Co., Ltd. |
| Gelatin | 5mg | Qinghai gelatin limited company |
| Cresol | 0.3mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Magnesium stearate | 0.6mg | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
| Gross weight | 199.91mg or 200.05mg |
Method for making:
(1) 0.14g cholecalciferol-cholesterol and 5g gelatin, 0.3g cresol heating for dissolving are cooled off, then crushing screening.
(2) in step (1) gained mixture, add 91.37g three water alendronic Acid list sodium salts, 40g Lactis Anhydrous, 56.5g microcrystalline Cellulose, 6gPVP-XL, mix homogeneously with the equivalent method of progressively increasing.
(3) in step (2) gained mixture, add the 0.6g magnesium stearate, mixed then 2 minutes.
(4) step (3) gained mixture is carried out the stamping of 8mm scrobicula, get tablet.
Embodiment 9: Alendronate sodium cholecalciferol-cholesterol oral administration solution
Specification: Alendronate sodium 70mg/0.14mg cholecalciferol-cholesterol (being equivalent to the 2800IU vitamin D3)
With Alendronate sodium 70mg/0.28mg cholecalciferol-cholesterol (being equivalent to the 5600IU vitamin D3)
Prescription:
| The supplementary material title | Every bottle of consumption | The source |
| Three water alendronic Acid list sodium salts | (91.37mg being equivalent to every Alendronate sodium that contains 70mg) | Shan Xi Han Jiang Pharmacy Co. Ltd |
| Cholecalciferol-cholesterol | 0.14mg or 0.28mg | Chongqing Kerui Pharmaceutical Co |
| Gelatin | 0.8g | Qinghai gelatin limited company |
| Tween 80 | 0.6g | The Zhejiang dragon emerging grain and oil medication chemistry company limited of getting together for fun |
| Arlacel-85 | 0.15 | Shen, Shanghai space medication chemistry company limited |
| B.H.A (tertiary butyl-4-hydroxy methoxybenzene) | 0.01g | Shen, Shanghai space medication chemistry company limited |
| Sodium benzoate | 0.03g | Hunan Er-kang Pharmaceutical Co., Ltd. |
| Water for injection | Add to 10ml |
Method for making:
(1) with 600g tween 80,150g Arlacel-85 and the heating of 800g gelatin, add 0.14g cholecalciferol-cholesterol and 10gBHA then, stirring and dissolving becomes solution A.
(2) 91.37g three water alendronic Acid list sodium salts and 30g sodium benzoate are dissolved with 5000g80 ℃ of water for injection, then gained solution is progressively added in the solution 1, stirred simultaneously 1 hour.
(3) continue progressively to add water for injection to 10000ml.
(4) with step (3) gained filled with solution to oral liquid bottle.
Embodiment 10: Alendronate sodium/cholecalciferol-cholesterol tablet (compound recipe), Alendronate sodium/vitamin D3 tablet (compound recipe) the two bioavailability relatively
Absorb
Alendronate sodium
(Merck company, the Alendronate sodium in 70mg/2800IU) is bioequivalent to Alendronate sodium/cholecalciferol-cholesterol tablet (embodiment 1) and Alendronate sodium/vitamin D3 sheet (compound recipe).Alendronate sodium in Alendronate sodium/cholecalciferol-cholesterol tablet (embodiment 1) and Alendronate sodium sheet (folk prescription) the 70-mg sheet is bioequivalent.
For referencial use with vein dosage, empty stomach and standard early gave Alendronate sodium 5-70mg in 2 hours before the meal, and its average oral administration biaavailability is 0.64% in the women, is 0.59% at the oral 10mg of male.
Cholecalciferol-cholesterol
Behind empty stomach and the standard administration Alendronate sodium/cholecalciferol-cholesterol tablet 2 hours before the meal morning (embodiment 1), baseline adjustment area under the blood plasma-concentration-time curve of vitamin D3 (AUC0-120 hour) is 120.7ng-hr/mL.The average maximum plasma concentration of the baseline adjustment of vitamin D3 (Cmax) is 4.0ng/mL, to baseline adjustment average time (Tmax) of maximum plasma concentration be 10.6 hours.The bioavailability of the vitamin D3 of the 2800IU in compound alendronate sodium/cholecalciferol-cholesterol tablet is similar with the bioavailability of taking the cholecalciferol-cholesterol slice that contains the 2800IU vitamin D3 separately, but is superior to taking separately the bioavailability of the vitamin D3 of 2800IU.
The baseline adjustment average A of vitamin D3 was respectively 355.6ng-hr/mL and 10.8ng/mL with the baseline adjustment mean Cmax in UC0-80 hour in the cholecalciferol-cholesterol.Baseline adjustment average T max is 9.2 hours.The bioavailability of the vitamin D3 of the 2800IU in compound alendronate sodium/cholecalciferol-cholesterol tablet is similar with the bioavailability of taking 5600IU vitamin D3 (cholecalciferol-cholesterol slices of two 2800IU vitamin D3 of administration) separately.
Distribute
Alendronate sodium
Preclinical study shows that after vein gave male rat Alendronate sodium 1mg/kg, its moment was distributed in soft tissue, but then is distributed in osseous tissue rapidly again or passes through homaluria.It except osseous tissue, is at least 28L at the intravital Vdss that is evenly distributed of people.The plasma protein binding rate of Alendronate sodium is about 78%.
Cholecalciferol-cholesterol
Vitamin D3 gets into blood as the part of chylomicron.Vitamin D3 distributes fast, and major part is distributed in liver and carries out metabolism, generates 25-hydroxy-vitamin D, promptly main storage form.Very small amount be distributed in fatty tissue with the stores of vitamin D3 in order to discharge into circulation later on.Circulation vitamin D3 and vitamin D-conjugated protein combination.
Metabolism
Alendronate sodium
Also there is not evidence to show that Alendronate sodium is at animal or human's internal metabolism.
Cholecalciferol-cholesterol
Vitamin D3 is 25-hydroxyvitamin D3 at liver by the hydroxylation tachymetabolism, and it is bioactive 1 then to be metabolised to tool at kidney, the 25-dihydroxy vitamin d3.Before eliminating, hydroxylation reaction can further take place, and other has the fraction vitamin D3 to carry out the glucosiduronic acid reaction.
Remove
Alendronate sodium
Disposable vein gives the Alendronate sodium of C14 labelling and finds that about 50% radioactivity by homaluria, did not have or had only the radioactive activity of very small amount in the feces in 72 hours.It is 71ml/min that disposable vein gives to measure its renal clearance behind the 10mg Alendronate sodium, and systemic clearance is no more than 200ml/min.Behind the intravenously administrable in 6 hours its PC descend more than 95%.Its t1/2 at human body estimates that greater than 10 years this prompting Alendronate sodium discharges from skeleton.Based on above-mentioned, the amount that is illustrated in the oral Alendronate sodium sheet Alendronate sodium that discharge from skeleton every day after (10mg every day) 10 years approximately is 25% of the amount that absorbs from gastrointestinal.
Cholecalciferol-cholesterol
When the quiet notes of the vitamin D3 of radioactivity were tried thing to health, the mean urinary removing amount of radioactivity was 2.4% of a dosage after 48 hours, and its average feces removing amount is 4.9% of a dosage.The vitamin D3 metabolite almost only removes through urine and excrement is removed.Behind oral administration compound alendronate sodium/dosage of cholecalciferol-cholesterol tablet, the mean half-life of the baseline adjustment of the vitamin D3 in the blood plasma is about 14 hours.
Sum up: (embodiment 1 for Alendronate sodium/cholecalciferol-cholesterol tablet; 70mg/2800IU), (each composition is all similar with the bioavailability of its folk prescription in the preparation for Merck company, the 70mg/2800IU) bioavailability of the two for Alendronate sodium/vitamin D3 tablet; But the bioavailability of cholecalciferol-cholesterol is superior to vitamin D3; Therefore generally, aspect bioavailability, Alendronate sodium/cholecalciferol-cholesterol tablet is superior to Alendronate sodium/vitamin D3 tablet.
Embodiment 11: Alendronate sodium/cholecalciferol-cholesterol tablet (embodiment 2,70mg/2800IU) and Alendronate sodium/vitamin D3 sheet (70mg/2800IU) curative effect relatively for import group, FOSAMAX PLUS D.
In the test in one 15 week; Object is from hospital outpatient and inpatient; 30 postmenopausal women and male; 71 years old mean age, suffer from osteoporosis (lumbar vertebra mineral density (BMD) is lower than 2.5 standard deviations of the meansigma methods menopause before at least), accept weekly perhaps FOSAMAX PLUS D (70mg/2800IU) weekly of Alendronate sodium/cholecalciferol-cholesterol tablet (70mg/2800IU) at random.Embodiment 2 compares with the import group, and its 25-hydroxy-vitamin D level and obvious effective rate are higher.
25-hydroxy-vitamin D terminal level and obvious effective rate after 15 weeks are added up in following table.
| The level of the 25-hydroxy-vitamin D in table 3 embodiment 2 or 15 weeks of import group treatment * | |||||
| 25-hydroxy-vitamin D average level (ng/ml) | Patient's percentage rate | ||||
| Before the treatment | After the treatment | Invalid | Effectively | Produce effects | |
| Embodiment 1 (N=15) | 15.06 | 20.43 | ?0 | ?6.7％ | 93.3％ |
| Alendronate sodium/vitamin D3 (N=15) | 15.12 | 18.46 | ?0 | ?13.3％ | 86.7％ |
Produce effects: alleviate fully
Effectively: the more original degree of pain alleviates over half
Invalid: as not have change or alleviation is arranged slightly
Embodiment 12: the curative effect of compound alendronate sodium/cholecalciferol-cholesterol tablet (embodiment 2) relatively
The patient who accomplishes above-mentioned 15 all fundamental test treatments has accepted the ensuing extended treatment in 24 weeks by a definite date; Everyone has accepted Alendronate sodium/cholecalciferol-cholesterol tablet, and (embodiment 2; 70mg/2800IU), and random arrangement accept additional weekly vitamin D3 2800IU and replenish (being vitamin D3 5600IU treatment group) or accept weekly placebo and replenish (being vitamin D3 2800IU treatment group).Behind the extended treatment in 24 weeks (promptly from on-test the 39th week back), be respectively 27.9ng/ml and 25.6ng/ml at the average level of the 25-hydroxy-vitamin D of vitamin D3 5600IU treatment group and vitamin D3 2800IU treatment group.Patient's ratio that two treatment groups are suffered from hypercalciuria in 39 weeks does not have difference on statistics.
Distribution in the final 25-hydroxy-vitamin D level that recorded in 39 weeks is summarised in table 2.
| The level of the 25-hydroxy-vitamin D in table 2 compound recipe or 39 weeks of folk prescription treatment * | ||||||
| Patient's case load and shared percent | ||||||
| 25-hydroxy-vitamin D scope (ng/ml) | ＜9 | 9-14 | 15-19 | 20-24 | 25-29 | 30-59 |
| The compound recipe group *(70mg/5600IU)(N＝321) | 0(1.1) | 10(3.1) | 29(9.0) | 79(24.6) | 87 (27.1) | 116 (36.1) |
| The compound recipe group **(70mg/2800IU)(N＝320) | 1(0.3) | 17(5.3) | 56(17.5) | 80(25.0) | 74 (23.1) | 92 (28.8) |
*The patient is follow-up with the Alendronate sodium/cholecalciferol-cholesterol tablet (70mg/2800IU) in 24 weeks and the extended treatment clinical trial of additional 2800IU vitamin D3 by a definite date for accepting 15 all Alendronate sodiums/cholecalciferol-cholesterol tablet (70mg/2800IU) fundamental test.
*The patient is the extended treatment clinical trial of the placebo of accepting follow-up Alendronate sodium/cholecalciferol-cholesterol tablet (70mg/2800IU) and the additional alternative vitamin D3 with 24 weeks by a definite date of 15 all Alendronate sodiums/cholecalciferol-cholesterol tablet (70mg/2800IU) fundamental test.
Claims (21)
1. pharmaceutical composition; It comprises the Alendronate sodium of 5-100 weight portion, cholecalciferol-cholesterol, 0.1-20 weight portion antioxidant and the pharmaceutically acceptable carrier of 0.1-0.5 weight portion, and said antioxidant is selected from cresol, tertiary butyl-4-hydroxy methoxybenzene, vitamins antioxidant, sodium pyrosulfite, L-cysteine hydrochloride, gallic acid second fat and EDTA-2Na.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, said pharmaceutically acceptable carrier is selected from filler, disintegrating agent, fluidizer, lubricant, binding agent and solvent.
3. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said Alendronate sodium is the 10-90 weight portion.
4. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said Alendronate sodium is the 10-80 weight portion.
5. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said Alendronate sodium is the 10-70 weight portion.
6. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said cholecalciferol-cholesterol is the 0.11-0.4 weight portion.
7. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said cholecalciferol-cholesterol is the 0.12-0.3 weight portion.
8. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said cholecalciferol-cholesterol is the 0.14-0.28 weight portion.
9. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said antioxidant is the 0.1-15 weight portion.
10. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said antioxidant is the 0.2-12 weight portion.
11. pharmaceutical composition as claimed in claim 1 is characterized in that, the consumption of said antioxidant is the 0.3-10 weight portion.
12. pharmaceutical composition as claimed in claim 1 is characterized in that, said pharmaceutical composition also comprises solubilizing agent.
13. pharmaceutical composition as claimed in claim 5 is characterized in that, the consumption of said solubilizing agent is the 1-2000 weight portion.
14. pharmaceutical composition as claimed in claim 5 is characterized in that, the consumption of said solubilizing agent is the 2-1800 weight portion.
15. pharmaceutical composition as claimed in claim 5 is characterized in that, the consumption of said solubilizing agent is the 3-1700 weight portion.
16. pharmaceutical composition as claimed in claim 5 is characterized in that, the consumption of said solubilizing agent is the 5-1550 weight portion.
17. pharmaceutical composition as claimed in claim 1 is characterized in that, the dosage form of said pharmaceutical composition is granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion or tincture.
18. pharmaceutical composition as claimed in claim 1 is characterized in that, the dosage form of said pharmaceutical composition is a suspension.
19. pharmaceutical composition as claimed in claim 1 is characterized in that, the dosage form of said pharmaceutical composition is a solution.
20. pharmaceutical composition as claimed in claim 1 is characterized in that, said vitamins antioxidant is selected from vitamin C or E.
21. the purposes of the described pharmaceutical composition of claim 1 in the osteoporotic medicine of preparation treatment.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710170980XA CN101444521B (en) | 2007-11-26 | 2007-11-26 | Pharmaceutical preparation containing alendronate sodium and cholecalciferol-cholesterol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710170980XA CN101444521B (en) | 2007-11-26 | 2007-11-26 | Pharmaceutical preparation containing alendronate sodium and cholecalciferol-cholesterol |
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| Publication Number | Publication Date |
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| CN101444521B true CN101444521B (en) | 2012-07-04 |
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| CN200710170980XA Active CN101444521B (en) | 2007-11-26 | 2007-11-26 | Pharmaceutical preparation containing alendronate sodium and cholecalciferol-cholesterol |
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| CN108420797B (en) * | 2018-05-09 | 2022-05-03 | 南京海融制药有限公司 | Vitamin D analogue preparation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074827A (en) * | 1992-01-27 | 1993-08-04 | 信谊药厂 | Cholecalciferol-cholesterol emulsion and preparation method thereof |
| CN1751690A (en) * | 2005-09-12 | 2006-03-29 | 广东先强药业有限公司 | Compound injection contg. alendronate sodium and vitamin D3 |
| CN1993134A (en) * | 2004-05-19 | 2007-07-04 | 默克公司 | Composition for inhibiting bone resorption comprising bisphosphoric acid (alendronic acid) and vitamin D (cholecalciferol) |
-
2007
- 2007-11-26 CN CN200710170980XA patent/CN101444521B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074827A (en) * | 1992-01-27 | 1993-08-04 | 信谊药厂 | Cholecalciferol-cholesterol emulsion and preparation method thereof |
| CN1993134A (en) * | 2004-05-19 | 2007-07-04 | 默克公司 | Composition for inhibiting bone resorption comprising bisphosphoric acid (alendronic acid) and vitamin D (cholecalciferol) |
| CN1751690A (en) * | 2005-09-12 | 2006-03-29 | 广东先强药业有限公司 | Compound injection contg. alendronate sodium and vitamin D3 |
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| CN101444521A (en) | 2009-06-03 |
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