JP2987334B2 - Stable vitamin B12-containing pharmaceutical particles and stable solid oral compound pharmaceutical preparation using the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to relates to pharmaceutical particles and solid oral complex pharmaceutical preparation using the same capable of stably blended vitamin B ₁₂ compound.

[0002]

BACKGROUND OF THE INVENTION Vitamin B ₁₂ compounds (cobalamin) is a vitamin containing cobalt is extremely effective in the treatment of pernicious anemia. It is known that vitamin B ₁₂ includes cyanocobalamin, hydroxocobalamin, acocobalamin, nitritocobalamin, methylcobalamin, and the like, depending on the type of ligand for cobalt.

[0003] Vitamin B ₁₂ compounds are themselves stability is known to be poor, are known several techniques of stabilization for using vitamin B ₁₂ as a medicament.

Conventionally, as a method for stabilizing an oral solid preparation containing vitamin B ₁₂ compounds, a method of coating a finely divided vitamin B ₁₂ such starch derivatives (JP 49-10822
No. 4), a method of dispersing the vitamin B ₁₂ compounds in a mixture of starch and dextrin (JP 3-173823
No.) etc. are known. As another method, frozen vitamin B ₁₂ compound with gelatin aqueous solution was adjusted thin sheet, a method of preparing a vitamin B ₁₂ analogue particles which are included the sheet was pulverized in a gelatin matrix also known ing.

[0005] However, the method using starch, its derivatives or dextrins has not been able to obtain sufficiently satisfactory stability and is not practical. on the other hand,
How to use the gelatin, the case of the vitamin B ₁₂ alone formulation but stability is obtained, the ratio of gelatin increases, cause problems due to the gelatin,
In addition, there is a problem in that the stability of a solid preparation formulated with other susceptible drugs, particularly other vitamins, is reduced.

[0006]

[SUMMARY OF THE INVENTION Accordingly, a suitable amount of gelatin, yet the development of stable formulations of vitamin B ₁₂ such possible formulations with other agents has been desired.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, adsorbing a mixed solution of vitamin B ₁₂ and gelatin on a powdered carrier has revealed that vitamin B ₁₂ Has been found to be able to be stably dispersed in a gelatin matrix, and if this is further coated, it can be stably blended with other drugs such as vitamin preparations, and thus completed the present invention.

Accordingly, the present invention provides a stable vitamin B characterized in that a mixed aqueous solution of vitamin B ₁₂ and gelatin is adsorbed on a powder carrier, dried, and then the adsorbate is coated with a coating material. It is intended to provide Class _12- containing drug particles. The present invention was formulated and pharmaceutical particles containing the vitamin B ₁₂ analog-containing pharmaceutical particles and other drugs, there is provided a stable solid oral complex pharmaceutical preparation.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION To prepare pharmaceutical particles containing vitamin B _{12 of the} present invention (hereinafter referred to as “vitamin B ₁₂ particles”), first, vitamin B ₁₂ and gelatin are dissolved in water,
It is necessary to adsorb this on a powder carrier. The vitamin B ₁₂ compound for use in the present invention, cyanocobalamin, hydroxocobalamin, Akokobaramin,
Nitritocobalamin, methylcobalamin and the like, and organic or inorganic salts thereof can be mentioned. It is preferable to use gelatin that has been subjected to an alkali treatment. Further, as the powder carrier, as long as capable of adsorbing vitamin B ₁₂ compound and gelatin, in particular can be used without limitation, preferred are crystalline cellulose, corn starch, D- mannitol,
Lactose, calcium hydrogen phosphate, partially pregelatinized starch, dextrin, light anhydrous silicic acid, and the like.

[0010] Next, the dry powder carrier with adsorbed vitamin B ₁₂ compound and gelatin. This drying step is preferably performed at a temperature as low as possible up to about 50 ° C. in consideration of the properties of vitamin B ₁₂ , and the granulated particles have a size of about 200 to 700 μm (particle diameter). It is preferable that the particles are sized.

The particles obtained are further coated with a coating. Gelatin,
Hydroxypropyl methylcellulose and the like.
The granulating and coating are, for example, after adsorption of vitamin B ₁₂ compound and gelatin, drying the treated particles (hereinafter, referred to as "adsorption particles") performed the solution of coating agent in the method of spray coating, adsorption particles What is necessary is just to make a coating layer having a thickness of about 10 to 50 μm thereon. The vitamin B ₁₂ particles thus obtained can be a stable vitamin B ₁₂ preparation by itself, but this is combined with particles containing other kinds of drugs (hereinafter referred to as “other kinds of drug particles”). In this way, excellent solid oral compound pharmaceutical preparations (hereinafter referred to as “composite drugs”
Is obtained.

[0012] In this composite pharmaceutical, vitamin B ₁₂ particles and combinations of the present invention, excellent Other species drug particles which effect is obtained, labile drug, for example, particles of drug that decomposition or alteration by the oxidation-reduction action And, in particular, particles of various vitamins exhibiting a medicinal effect by a redox action in a living body.

[0013] The composite medicament is prepared by formulating a mixing ratio necessary for a vitamin B ₁₂ particles and other species drug particles. Examples of the preparation include composite granules and fine granules simply obtained by mixing both types of pharmaceutical particles, and composite tablets obtained by compressing the same in a conventional manner.

[0014]

Vitamin B ₁₂ particles and composite pharmaceutical stable reason of the action of the present invention is believed to be due to the following mechanism. That is, a mixed aqueous solution of vitamin B ₁₂ compound and the gelatin adsorbed on the powder carrier, by drying, the sheet as well as gelatin matrix obtained by freezing the mixed solution is considered to be obtained, further coating the surface to a result, vitamin B _12, which is formulated is not exposed to the outside is considered as being itself stably maintained. Since the vitamin B _{12 of} the vitamin B ₁₂ particles is not exposed to the outside, it is considered that the vitamin B ₁₂ does not interact with the drug component contained in the other drug particles, and can be stably stored as a complex drug.

[0015]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples.

Example 1 A multivitamin tablet containing hydroxocobalamin acetate stably was produced by the following composition and production method.

[Assembly] (Granulated product I) Unit amount Hydroxocobalamin acetate 0.52 mg Gelatin 10 mg Crystalline cellulose 20.48 mg Subtotal 31. mg (Granulated product II) Fursultiamine hydrochloride 36 mg Tocopherol succinate Calcium 35 mg Nicotinamide 6 mg Crystalline cellulose 53 mg Hydroxypropyl cellulose 3 mg Subtotal 133 mg Carboxymethyl starch 9 mg Sodium hardened oil 5 mg Light silicic anhydride 2 mg Total 180 mg

[Production Method] First, hydroxocobalamin acetate and a part of gelatin are dissolved in purified water, adsorbed on crystalline cellulose, and dried. The adsorbed product is further spray-coated with the remaining gelatin dissolved in purified water. This is dried to obtain granulated product I. Next, the four components from fursultiamine hydrochloride to crystalline cellulose are mixed and granulated with an ethanol solution of hydroxypropylcellulose. This is dried to obtain granulated product II. The obtained granulated product I and granulated product II are mixed, and sodium carboxymethyl starch, hydrogenated oil, and light anhydrous silicic acid are added to the mixture, and the mixture is tableted to produce tablets.

Example 2 A multivitamin tablet stably containing hydroxocobalamin acetate was produced by the following composition and production method.

[Composition] (Granulated product I) Unit amount Hydroxocobalamin acetate 0.52 mg Gelatin 5 mg Hydroxypropyl methylcellulose 8 mg Crystalline cellulose 21.48 mg Subtotal 35 mg (Granulated product II) Bisbenamine 30 mg Pyridoxine hydrochloride 30 mg d-α-tocopherol succinate 30 mg Microcrystalline cellulose 35 mg Hydroxypropylcellulose 3 mg Subtotal 128 mg Carboxymethyl starch 10 mg Sodium hardened oil 5 mg Light silicic anhydride 2 mg Total 180 mg

[Production Method] First, hydroxocobalamin acetate and gelatin are dissolved in purified water, adsorbed on crystalline cellulose, and dried. The adsorbed product is spray-coated with a solution of hydroxypropylmethylcellulose dissolved in purified water. This is dried to obtain granulated product I. Next, four components from bisbenthamine to crystalline cellulose are mixed and granulated with an ethanol solution of hydroxypropylcellulose. This is dried to obtain granulated product II. The granulated product I and the granulated product II are mixed, and sodium carboxymethyl starch, hydrogenated oil and light anhydrous silicic acid are added to the mixture, and the mixture is compressed into tablets.

REFERENCE EXAMPLE 1 A complex vitamin tablet containing hydroxocobalamin acetate was produced by the following composition and production method.

[Assembly] (Granulated product I) Unit amount Hydroxocobalamin acetate 0.52 mg Crystalline cellulose 15.18 mg Hydroxypropyl cellulose 0.3 mg Subtotal 16 mg (Granulated product II) Flusultiamine hydrochloride 37 mg Microcrystalline cellulose 110 mg Hydroxypropyl cellulose 3 mg Subtotal 150 mg Carboxymethyl starch 7 mg Sodium hardening oil 4 mg Light silicic anhydride 3 mg Total 180 mg

[Production Method] First, two components of hydroxocobalamin acetate and crystalline cellulose are mixed and granulated with an ethanol solution of hydroxypropyl cellulose. This is dried to obtain granulated product I. Next, the two components of fursultiamine hydrochloride and crystalline cellulose are mixed, and granulated with an ethanol solution of hydroxypropylcellulose.
This is dried to obtain granulated product II. The obtained granulated product I and granulated product II are mixed, and sodium carboxymethyl starch, hydrogenated oil, and light anhydrous silicic acid are added to the mixture, and the mixture is tableted to produce tablets.

REFERENCE EXAMPLE 2 A multivitamin tablet containing hydroxocobalamin acetate was produced by the following composition and production method.

[Assembly] (Granulated product I) Unit amount Hydroxocobalamin acetate 0.52 mg D-mannitol 18.98 mg Hydroxypropylcellulose 0.5 mg Subtotal 20 mg (Granulated product II) Fursultiamine hydrochloride 36 mg Pyridoxine hydrochloride 33 mg Crystalline cellulose 76 mg Hydroxypropyl cellulose 3 mg Subtotal 148 mg Carboxymethyl starch sodium 5 mg Hardened oil 4 mg Light silicic anhydride 3 mg Total 180 mg

[Production Method] First, two components of hydroxocobalamin acetate and D-mannitol are mixed and granulated with an ethanol solution of hydroxypropylcellulose.
This is dried to obtain granulated product I. Next, the three components from fursultiamine hydrochloride to crystalline cellulose are mixed and granulated with an ethanol solution of hydroxypropylcellulose. This is dried to obtain granulated product II. The obtained granulated product I and granulated product II are mixed, and sodium carboxymethyl starch, hydrogenated oil, and light anhydrous silicic acid are added to the mixture, and the mixture is tableted to produce tablets.

REFERENCE EXAMPLE 3 A multivitamin tablet containing hydroxocobalamin acetate was produced by the following composition and production method.

[Composition] (Granulated product I) Unit amount Hydroxocobalamin acetate 0.52 mg Gelatin 10 mg Crystalline cellulose 5.48 mg Subtotal 16 mg (Granulated product II) Bisbenthamine 33 mg Nicotinamide 6 mg Crystalline cellulose 106 mg Hydroxypropyl cellulose 3 mg Subtotal 148 mg Carboxymethyl starch sodium 9 mg Hardening oil 5 mg Light anhydrous silicic acid 2 mg Total 180 mg

[Production Method] First, two components of hydroxocobalamin acetate and gelatin are dissolved in purified water and adsorbed on crystalline cellulose. This is dried to obtain granulated product I. Next, the three components from bisbenthamine to crystalline cellulose are mixed and granulated with an ethanol solution of hydroxypropylcellulose. This is dried to obtain granulated product II. The obtained granulated product I and granulated product II were mixed, and sodium carboxymethyl starch, hydrogenated oil,
Light anhydrous silicic acid is added and the mixture is compressed into tablets.

TEST EXAMPLE Severity test: The complex vitamin tablets prepared in Examples 1 and 2 and Reference Examples 1 to 3 were subjected to a severe test at 50 ° C. and 60 ° C. for 1 week, and then hydroxocobalamin acetate. Was measured. Table 1 shows the results.

[0032]

[Table 1] As is evident from the results, it was confirmed that the multivitamin preparation prepared using the vitamin B ₁₂ particles of the present invention could maintain stability even under the harsh condition of holding at 60 ° C. for one week. Was done.

[0033]

According to the present invention, when the vitamin B ₁₂ particles are used,
It is possible to provide a stable vitamin B ₁₂ preparation. Further, by combining the vitamin B ₁₂ particles with other pharmaceutical-containing particles, it is possible to prepare a stable complex pharmaceutical. that's all

Continuation of the front page (56) References JP-A-1-203329 (JP, A) JP-A-49-108224 (JP, A) JP-A-59-152327 (JP, A) JP-A-3-173823 (JP) , A) JP-B-45-12759 (JP, B1) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/68

Claims (6)

(57) [Claims] After a 1. A vitamin B ₁₂ compound with a mixed aqueous solution of gelatin was adsorbed on a powder carrier, which is dried, then ₁₂ such stable vitamin B content, characterized in that coating the adsorbate with a coating agent Pharmaceutical particles. Wherein the coating agent is gelatin or hydroxypropylmethyl cellulose claim stable vitamin B ₁₂ analog-containing particle of any preceding claim. Wherein the vitamin B ₁₂ compound is acetic hydroxocobalamin claim paragraph 1 or stable vitamin B ₁₂ analog-containing particles of the second Claims. 4. The powder carrier according to claim 1, wherein the powder carrier is selected from the group consisting of crystalline cellulose, corn starch, D-mannitol, lactose, calcium hydrogen phosphate, partially pregelatinized starch, dextrin and light silicic anhydride.
Item 4. The stable vitamin B according to any one of items 3 to 3.
Class ₁₂ containing particles. 5. The stable vitamin B _{12 according to} claim 1,
A stable solid oral composite pharmaceutical preparation comprising a class of drug particles and a drug particle containing another drug. 6. A stable solid oral complex pharmaceutical preparation according to claim 5 wherein wherein the other agent is an vitamins other than vitamin B ₁₂ compound.