JPS5877811A - Preparation of stable and easily absorbable pharmaceutical preparation of nifedipine - Google Patents

Abstract

PURPOSE:To prepare the titled pharmaceutical preparation useful for remedying breast pang, obtained by coating a fine particle carrier made of a water-soluble drug additive with a solid solution of nifedipine and hydroxypropylmethyl cellulose or methyl cellulose. CONSTITUTION:A water-soluble drug additive (e.g., lactose, white sugar, glucose) is blended with an aqueous solution of a binder (e.g., hydroxypropyl cellulose, gelatin) and granulated to give a fine particle carrier, which is coated with a solid solution of nifedipine and hydroxypropylmethyl cellulose or methyl cellulose in a weight ratio of 1:(2-5) to give the titled pharmaceutical preparation. The uniform coating is required, preferably a solution of the solid solution is formed by using a mixed solvent of ethanol and dichloromethane, and it is subjected to spray coating by a fluidized bed granulator, etc. The pharmaceutical preparation has good solubility of nifedipine to water and improved absorption into the body, having stability to moisture.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing stable and easily absorbable Nianidipine, and more specifically, the present invention relates to a method for producing stable and easily absorbable Nianidipine. A highly absorbable and stable nianidibin formulation characterized by coating with a #lA solution consisting of cellulose (hereinafter referred to as npmc) or methyl cellulose (hereinafter referred to as FμC)! &!
Regarding the law.

Nianidipine has a coronary vasodilatory effect and is an excellent treatment for angina pectoris attacks, but KFi preparations are easy to take and are rapidly absorbed into the body after taking. It has to be something.

Nianidipine is a crystal that dissolves in water, and even if its powder is used as ordinary l1lI11, it is poorly absorbed into the body and does not meet the above-mentioned requirements, which may cause angina attacks.

Therefore, a means to improve the malabsorption property of near s-dipine-0
As one, nifedipine and polyvinylpyro + 1 ton (
PVP (hereinafter referred to as h) is dissolved in an organic solvent, the organic solvent is distilled off from the melt ridge, and the resulting solid solution consisting of nianidibin and pvp is used as a beverage or as a granule. @tpvpk! ! Made of liquid powder - Yoshitsugu Hibari? ] The method to do this is to be
No. 854-2516. f) The dissolution and absorption properties of the PVPgg body powder (comparative formulation A) are improved compared to simple Nianidipine powder, but it is not sufficient for wood.

On the other hand, the present inventors have developed a further improved 1
As a result of various studies in the ninth stage of obtaining 1J, we dissolved nianidipine v-1 in an organic solvent Kflj, poured this #1 solution onto crystalline lactose, dried it, and coated it uniformly with an am-form consisting of nianidipine and pvp. Nine Fine Grain Yoshitsugu [Hereafter, this kind of preparation is PVP-solution coated Yoshitsugu [#, Comparative @K]
)] (Chemical Press, Vol. 29, pp. 1715-1725, 1981). This pvplIm#1 body coating milling (comparative milling mouth) was performed using the PVP disol powder dissection (
Compared to It@II@I), it has a weaker Kik elution rate and is easily absorbed, and is much more effective in the treatment of angina pectoris attacks. However, when this product is left in high humidity, the dissolution of nifedipine from the preparation into water decreases (see Figure 111113.186). Not only that, MG protection is required for the IMVC manufactured as well.

The inventors described the above pvplI! N1 solution coating machining (Comparison! 1! Tsuguguchi)'s head point f: Results of study to improve: ICL (PMC*taiJ) instead of pvp
Adopt MC, granulate the water-soluble medicine: fI additives, and granulate the C Sakaki fine particle carrier with Nianidipine and HPMC IIIJ.
We have invented a method for uniformly coating with a solution or a 1# solution of nianidipine and MC.

Nifedipine and HPMC produced by the method of the present invention
Fine grains 11A4J coated with Is solution (hereinafter)
'HI' MC day solution coating autopsy) and ii with Nianidipine and MO! Fine grains coated with Il solution
Nianidipine's dissolution into water or absorption into the body is comparable to that of #1 pvp H solution coach 4-ring autopsy (comparative cutting mouth), and it is more effective against wrinkles than Le Kamo tI. It is stable.

The method of the present invention includes the step of preparing a fine particle carrier made of a water-soluble pharmaceutical additive, and preparing a solution of a solid solution of nianidipine and HPMC in an organic solvent or a solution of nianidipine and MO in one solution. and uniformly coating a fine particle carrier with the nifedipine solid solution solution.

Each step will be explained below.

First, the fine particles and the final Il in the manufacturing process of the fine particle carrier in the present invention! Fine grains in grinding are defined as those in the particle size range defined in the Japanese Pharmacopoeia General Rules.

The fine particle carrier of the present invention is a combination of water fgH and a water-soluble pharmaceutical additive such as lactose, sucrose, glucose, etc. -J.

For example, ζ droxyglopy cellulose, HPMC.

PVP, polyvinyl alcohol, gum arabic, gelatin, etc. are blended, more preferably an alkyl sulfate, dialkyl sulfosuccinate, etc. are blended, and ζ granules are produced according to a conventional method9. , slow granulation method, dry granulation method, flow #-granulation method, transfer 11Mk
Although the granulation method and other commonly used methods may be used, the tIL#-granulation method or the transmission granulation method is also preferable for eels. However, if a surfactant is further added, the amount of
If it is about 596, it is good.

Next, nifedipine 1d #1 body flI/& is Nianidipine and HPMC or Nianilevin and Yari, C total 44 Iso fg
Medium tL
HPM that can be prepared by dissolving in /,) and being here now...
C is the 10th revised Japanese Pharmacopoeia's [Hydroxypropy!
-Methylcellose 2208J, ``Mukai 2zoJ r1
42910J was shot, and ``methyl cellulose'', which is used as a MO and C, was mentioned.

Former 1C and 111Cc/) usage side (11 amount ratio) for nifedipine.

If the 141i imprint for Nianidipine is below the lower limit of the E range (P'MC)
・O・and ratio #II! l! 2) #i, In the next step, the t-fing step, Nianidipine deposits are precipitated on the surface of the fine carrier, and the dissolution of Nifedipine from the drug into water is low (Fig. 2). , !5 figure nursing). On the other hand, the old IC Matata
If fMc is used above the upper limit of the above range, it will only make the @-shape larger), thereby increasing the near j
It is not possible to improve the dissolution properties of L-dipine.

Next, use ethanol-dichloromethane (1:IW/W) to be used in the nifedipine solution solution, and add 1.2 to 1.5 times the amount required to completely dissolve nifedipine and HPMC at room temperature. is appropriate.

Finally, in the present invention, the fine-grained carrier must be coated with the nifedipine solid solution to a toe and uniformly. Therefore, in the coating process, the fine-grained carrier must be
It is recommended to uniformly add a predetermined amount of a 2□7-dipine solid solution solution to this while maintaining the IK[lIl state] and dry it. Specifically, 1@ for the production of normal fine grains and fine grains.
- It is preferable to perform a spray coating operation in a rolling granulator when the tIL-interrupted granulation ridge is used.

In this case, if the conditions are nt, the amount of injection Ill per unit time is 6
What are the requirements for manufacturing ordinary grains and fine grains, such as the degree of tsubo, flow resistance of fine grain carriers, etc.? F can be applied mutatis mutandis.

By adopting such a coating method, it is possible to uniformly coat with a predetermined amount of nifedipine solid solution while preventing the crushing and mutual bonding of the raw fine particle carrier,
Moreover, it is easy to operate and has good work interference.

The product of the present invention obtained as described above has a quality of 111r.

First, the absorption trap of nianidipine into the living body when administered orally, and the former 1C solid solution of the present invention
1lIJ (Book@#411114 A-2) & YoU
111C-Solution Coating Ii! The machining (IP1 machining B-2 produced by the present invention) is significantly superior to the pvp @ solution powder machining-1 A), and is almost as easy as the pvy solid solution coach Zung Yoshitsugu (comparative formulation mouth). It is absorbable (sample blind, see Figure 1).

Second, the formulations of the present invention are not unstable to the impact of the pvp solid solution coated formulation (comparison mill).

pvp solid solution coating Il! Cutting (comparative 1110)
is stable under low-strength conditions, but when left in a high-strength condition, e.g., at a relative strength of 75%, the dissolution of nianidipine is significantly inhibited (Example 5, 6 nursing care). On the other hand, HPMC-solution coated Yoshitsugu of the present invention (present invention Yoshitsugu-2) and kC-solution coated IiI shaved (present invention formulation 8-2) both showed high yield even when left under the above humidity conditions. V-& (Test Example 5. Figure 114, @Figure 5 Nursing Care II)
.

The stability of the present invention is expected to be beneficial not only in storage and emulsion of the preparation, but also in the formulation process.

The implementation St will be listed and explained below.

Reference Example 1 Production of pvp@Soluble Powder Manufacturing Procedures (A) Production of Lactose Dissolved OfK, tl''Lokin Propy #4 Loin 20111'
Dissolve VP 50fν and Niphelipin 500ml in ethanol and add to it using an all-purpose mixing stirrer (product 111).
After kneading in a 8DMV-R model (manufactured by T Industry Co., Ltd.), the mixture was extruded and granulated using a No. 05 Shizu screen, and dried on a shelf at 60°C. This was sized with a -52 mesh.

The fine particle carrier qtuvkHA of Example 1 described later was mixed with nianidipine IOf and PVP30f with ethanol-dichloromethane (1: + '/, ) s ol)-
Spray coating was carried out in the same manner as in Example 1 using an fs solution dissolved in .

Example 1 Upwca solution coating pleats (manufactured by the present invention)
1, A-2, A-5, A-4)! l! Production (1) Production flow of fine particle carrier! lI granulation dryer (Glatt OkawaIr)
950 parts of lactose was added to a W2O-1 type, and a solution of hydroxypropylcellulose 208B dissolved in 500 parts of water was sprayed onto it, granulated and dried. obtain.

(2) Coating HPMCi of the present invention by the following six methods and methods. Solution coating manufacturing (invention manufacturing ^-1, A-2, A-5,
^-4) and comparative 111 pieces were prepared, 90 predetermined amounts of Niani Jibishi and HI'MO were dissolved in 500-2 tanol-dichloromethane (1:l), and the fluidized bed granulation ridge (6
Add this #1W to a predetermined amount of the nine fine particle carrier obtained in (1) at 0°C).
11 to 1 (spout III degree 10/υ-/- eight dry ruts, 3
I took 1 pill with 2 metsushi 21.

100-body Kohli 4 Ring II @ (Zero-based production II B implementation @ 2゜-1, B-2, B-5, "Production (1) of fine particle carrier Example 1 (1) #!

(2) Using VC instead of HPMC in Coating Example 1, and using the same FIA method as in Example 1 according to the following six methods (coach test example), a Peagle dog fasted overnight [body weight 8 ~12 to 9) The above-mentioned invention fabrication A-2, invention fabrication B-2, pvpWf to 4 animals
G-body wood machining (comparative machining, PvF 6J solution coating *1 IIJ (comparative machining Ron's): An amount equivalent to 1% T of Fesihin ILIj was orally administered.

Samples were taken at each time point of 120 and 240 minutes after injection, and the concentration of nianidibin in the plasma was determined by biCO gas chromatography, and the results shown in Figure 111 were obtained.

As shown in Fig. 1, upucW solution coating machining (Honryoshi Tsuguma ^-2) and -cfll solution coating, PVPfi@body coating I! l! It is comparable to that of iJ (comparative cutting a).

Test Example 2゜Nianigibin elution test σBK' We used a method of refluxing the water with a bong to a slow J.

Fi distilled water 500- was used as the eluent9, and this was 37±
α150 using a 4-blade stirring propeller while maintaining the temperature at 5°C.
Stir at a speed of rp-.

In this eluate, 1. A sample containing 50 qK of Nianizibin was added, and the elution amount was determined by determining the difference in absorbance at 525 am+ 4 and 5 (10 nm). 4) and the ratio 1m!I!M2 Nianizibin dissolution test is shown.

1121m- and Fig. 3, the use of ipwc or fiisc for Nianijibi*#i Nianidipine 1 part by weight KM and 1 part by weight are required, and 2 to
It is preferably 5 parts by weight compared to the weight of S.

Inspection and Ik test for stability against all at once Put brass wadori salt in a cage and keep it at 40°C. The dissolution of each sample in water was examined using 111F of each sample.

fl14mltMPwOW4111bodyM-yriin9
"Preparation C main phrase tRm@mu-2) 66 output properties, Figure 115 shows MC solid solution coating Ipl (made by the present invention B-2)
The solubility ratio of width 6 ■ company vvp @ solution booting piece (
In each figure, the curve 41m (vh) indicates the initial dissolution, the curve C indicates the dissolution after storage for 1 month, and the - line C indicates the dissolution after storage for 6 months.

As shown in Fig. 6, the dissolution of nianidipine significantly decreases within one month of storage in the pvp solid solution coated keratin (114 keratin).

This is KNL, lI! As shown in Figure 4 and Figure 5,
IIPMcIII @ body coating manufacturing (present invention formulation Yoshitsugu 2) and MCI! ! In Il solution coating machining (Yoshitsugu of the present invention @ 5-2), after 5γ months of storage,
− However, there is no noticeable change in the dissolution properties of nianidipine.

[Brief explanation of the drawing]

Figure 111 shows the results of the blood concentration of Nianidipine during the course of oral administration of Nianidipine l' Ill described in F. IF Rei cmfl 1 body coaching 4 manufacturing (Preparation of the present invention A-
2) mCts happy body footing (preparation B of the present invention)
-2) Furnace VP-molten wheel wheel 11ri11 (comparative manufacturing method) tvpiiiin body coaching 4 manufacturing product 111J (
It-10) 111v4K? The vertical axis shows blood nianidipine my (nf/d), and the horizontal axis shows the elapsed time (minutes) from the time of oral administration to the time of blood collection. Figures 2 and 3 show HPMC solid solution solid solution Cong formulations (preparations of the present invention A-1, ^-2, ^-6, A
-4), MC solid solution coating manufactured preparation of the present invention 8-
1. B-2% B-3, B-4) and Yoshitsugu Yoshikari, Comparative II@2) We accept the results of the nifedipine dissolution test. Figures 4, 5, and 6 are ten Rizono HP-YC prison solution coatings! Il cutting (invention-%@A-2), MC
m5 body coating and cutting (Powder Meibutsu B-2). Made of PVIII solution coating @ (Comparison Ii! Lock)
A dissolution test of Nianidipine when stored at 40°C with a humidity of about 75°C is shown. In each figure, the song W
aFi initial #1 release properties, curve C shows the dissolution properties after one month of storage, and curve C shows the dissolution properties after three months of storage. In the above Figures @4 to W16, the vertical axis shows the amount of Il released into water (sl 1500 at ) of nifedipine, and the horizontal axis shows fs time (minutes). 1st verse 1. Fu, shipping.

Claims (1)

[Claims] (1B) A stable S@ characterized by coating a fine granular carrier obtained by granulating a water-soluble pharmaceutical additive with a monodissolved solution of nifedipine and hydroxypropyl and methylcellulose before lulose. Collection It=7E, DipinIll
Cutting method. (2) Special IfF arrogance range 1lIl in which the fil solution is composed of nifedipine to hytroxypropyl methylcellulose or methylcellulose in a ratio of 1=2 to 5 (weight ratio)
Method described in lK% section. (5) Claim 1, characterized in that Nianidipine and hydroxypropyl methylcellulose are added to the fine particle carrier obtained by granulating a water-soluble medical additive. O Method +41 11 The method described in Section 5 of Hayashi I of Patent No. 14, in which the solvent is a mixture of ethanol and dichloromethane.