JPS5951223A - Pharmaceutical composition - Google Patents

Abstract

PURPOSE:To provide a pharmaceutical preparation meeting the Japanese Pharmacopoeia, and capable of controlling the dissolution rate of the drug at various pH ranges, by coating a granule or tablet containing a sucrose fatty acid ester with a mixture of a polymer insoluble in water or soluble in gastric juice and a polymer soluble in water, and applying an enteric coating to the coated granule, etc. CONSTITUTION:A granule or tablet containing 2-50W/W% of sucrose fatty acid ester is coated with a mixture of (A) a polymer insoluble in water or soluble in gastric juice (e.g. alkyl cellulose derivative) and (B) a water-soluble polymer (e.g. cellulose ether derivative) preferably a ratio (B:A) of 0.25-1, and the coated granule, etc. is further coated with an enteric coating (e.g. shellac) to obtain the objective pharmacological preparation. The dissolution of the drug component at various pH ranges between 5-8 can be effectively controlled, and the obtained preparation meets the disintegration test of enteric coated tablet of the Japanese Pharmacopoeia.

Description

[Detailed description of the invention] The 1st son from To is able to adjust the R1 river of the 11th thing in P11'5-8 name 11 Summer 11: own JI East, and the 1st O change 11
:, Japanese Pharmacopoeia (hereinafter abbreviated as 10th edition) enteric coated 4f11
Decomposition of the agent d.

Generally medicine 6! It is desirable to maintain the blood organization level of the i-sexual component for a long period of 1 g after a certain amount of buffalo. There are many manufacturing methods for sustained release of active ingredients! However, no drug has been found that effectively fulfills the purpose of stably controlling the formation of drugs in each P111 shellfish region, and also meets the disintegration theory of enteric coating II+II.

Conventional manufacturing methods and 17 methods are more economical, such as coating the drug with a water-insoluble film or trapping it in an insoluble matrix by granulation. Although the objective of sustained release has been achieved, it is possible to control the elution at pH 10.
There are no products that meet the disintegration test theory for the 1st aid M's preparation.

Regarding the sustained release of pharmaceutical active ingredients, please refer to Basic Drug Development Course
The first exhaustion of l+ and the substances used therein are described. ＋＋＋Badōrenofu ni 1-ilHhi-11
15-Kawaichisa-Wa-ru-ichi-substance-Quality/Koto-Kan-J-4'L Management 47 For example, substances used in sustained release preparations include paraffin, il
Non-16IC substances in water such as N+ class alcohols and cellulose derivatives (ethylcellulose): sucrose fatty acid esters Jj'r costal acid monoglycerides, polyoxyethylene fatty acid esters, polyoxyethylene higher alcohols 1L In any water, J with φIn ) is the argument II! 1
Water-soluble substances such as polyhinyl alcohol, polyhinyl pyrrolidone, and macrochol: white medium lac, cellulose acetate phthalate, co-10 complex of methyl methacrylate l/=l- and methacrylic acid, etc. People have been making fun of enteric-coated polymers, but is this you? ^Mi to t<t made 11
The composition does not have sufficient functionality as a soluble sustained release preparation.

Unexamined Japanese Patent Publication No. +17-156-164114 includes +l:
f + starchy fatty acid and/or its metal stone in the whole preparation fi
It has a content of 1096 to 5096 relative to t, and is hk type regardless of impact compression. There is a description of Xu BK Jianhu, who was revised. Meat (7 first higher fatty acid and 7 or its 6z string salt used in the publication) 7A
Teha P II 5-80) each 1'll (g''
J, the elution of the drug could not be determined at δ111, and 10 stations, i
ll, collapse of 1 litho cutting outside the bath i+t; 111 also for hit
It doesn't match.

IJ old 1i'155 49812 publication describes instantly disintegrating grains in wax, water bathing properties ii: I1 molecules and II I, Yokuchika 9 or more 4 toy ionic surfactants fp ill, polar limbs Kl A method for preparing slow-release preparations is described, which is characterized in that after 7 days, the coating is compressed into tablets. Although there is no difference in the frI production rate in the diurnal 1 ict and the diurnal r1421+'k using the manufacturing method of this pH publication, the collapse of the 10 stations 11u+ target 4'l plate ill'
:It does not fit the theory17.

4i) Billr (57586 fl l +3 publication, IJ gastric fluid and IIjA fluid inbathless Ii': 1 molecule coating agent or intestinal m-soluble polymer covering All and gastric soluble commercial branch i\i A"l or A limb covering composition is described which comprises water fN 41 and a polymer monolayer.

In the case of the public gazette, 1" Honkuwa 1i'if force Gl゛) +? (2nd (delay of drug elution in Ck 111)
Is it possible to obtain uniform 4j All from J Mira Jl'? 111
Topical enteric coating 'l'1. Collapse of IJda 111) (
Not suitable for Aya/Roku.

As a result of intensive investigation into the above problem, the present inventors coated granules or tablets containing sucrose fatty acid ester with a mixture of a water-insoluble or gastric soluble polymeric substance and a water-soluble polymeric substance, and further coated them with enteric coating. By applying this method, we discovered a formulation that is capable of controlling the elution of drugs in each PH region and is compatible with 10-part enteric-coated formulations, and completed the present invention.

Examples of pharmaceutical active ingredients to which the present invention can be effectively applied include benziclane fumarate, indomethacin, indoprofen, mefenamic acid, flufenamic acid, methiazine acid, diclofenac, ibuprofen, ibufenac, Examples include alklofenanaloc, -ptekalone, flurbiprofen, phenylbutacin, oxyphenbutacin, and ketofiniruftazone.

The preparation of core granules and uncoated tablets can be carried out by commonly used known methods, but the sucrose fatty acid esters used in the present invention include lauric acid, myristic acid,
High grade 11W+IU t& esters such as palmitic acid, stearic acid, oleic acid, linoleic acid or beef tallow, 11111)-f, lanolin, coconut oil, castor oil,
There are esters of mixed fatty acids such as safflower oil and their hydrogenated oils, and those with an IIL of 132 to 16 are preferred, but for cattle, 1 is preferred, and 17 is preferably 2 to 5. Sucrose fatty acid ester is expected to form a nest in a low lji'i range of l'II (acidic example) and hinder the leaching of the drug.

"Addition of sucrose fatty acid ester" is applied to all cars manufactured by 'A11 n1.
2”/w 9= ~50”/w 96 (
1ri range”Q 7) tte J.

In particular, the range of 5 W/w 96 to 38 W/w 96 is particularly advantageous for achieving the object of the present invention. 2 W/w
If it is less than 5%, the effect will not be sufficient (5 (l W/w 96
Exceeding this will strengthen the young fruit too much.
l It will no longer meet the disintegration test. However, it goes without saying that the range of dosage is not necessarily absolute, and it is necessary to adjust the addition 111 according to the drug's properties and behavior in vivo.

In this way, 74/ta4'A condyle Th? Alternatively, coating of uncoated tablets can be carried out by commonly used known methods Vζ, but in the present invention, 1- Water-insoluble or curing-resistant high-quality substances used include alkyl celluloses such as methyl cellulose and butyl cellulose, ethyl acrylate, Methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer
] - Mu Pharma Inc. I! J), styrene-divinylbenzene copolymer, cellulose acetate dibutylaminohydride oxybrobyl ether, butyl methacrylate
1-Medimethylaminoether methacrylate-methacrylic acid ester copolymer (Eudragit E),
Polyvinyl acetal diethylaminoacetate, etc. can be used. On the other hand, as the water bathing polymer negative, for example, cellulose ethers such as hydroxybropylulerulose, methyl cellulose, carboxymethinosylulose putriuno 1, hydroxyethyl cellulose, and hydroxytulopyl methyl cellulose can be used. Ilk conductor: Starch moe 3-stops such as hydroxypropyl starch-hinyl 1t7f 39 bodies such as polyvinyl alcohol are obtained J).

Note that the water-insoluble or l#-soluble used in the present invention, 1°
The appropriate amount of the water bathing polymer for the 16-molecule compound is 0.25 to 1. More preferably 0
．． 83 to 0.5 is the ji value o/&, I conversion 11: 2 to 10% is appropriate, more preferably 8 to 7%, based on the nucleated grains.

Other additives include conventional fd% enrichment formulations, such as lactose, starch, mannitol, sorbitol, dextrin, calcium sulfate, etc. The Al1 composition of the present invention is a preparation obtained as described above. Known enteric coatings on the surface of shellac, ff+
; Cellulose acid phthalate, hydroxypropyl methyl cellulose phthalate-1 (quotient + V + name: II I' 5
5: Copolymer of methyl methacrylate-1 and methacrylic acid (Eudragit [F]L or 8L copolymer of methacrylic acid and ethyl acrylate (Eudragit LaO2)-55 )%
Carboxymethylethyl cellulose, methyl acrylate-methacrylic acid copolymer (trade name + M P M (
15: Is it intestinal laxative due to Sankyo Co., Ltd. M) etc? lk m. These drugs begin to release the heavy components of the drug only after the drug has passed, but the release is due to the added sucrose fatty acid esters, water-insoluble or water-increasing solubility, water-soluble molecular substances, and water-soluble polymers. 11 to the film of the mixture and the enteric film J: sl) II Each L of 5 to 8
)■ The elution of the drug in the region is effectively suppressed and
0゛It is a formulation compatible with one topical enteric coated drug.

The characteristics of wooden AI are that in the acidic region, elution is inhibited by the aggregation of sucrose fatty acid ester, water-insoluble polymeric substances, and enteric coat agent, while in the alkaline region So, water-insoluble F-? i3. ) The point is that the elution is controlled by the child substance or the soluble polymer it, making it possible to self-effectively control the elution of v)H' in the P11 region of P115-8. .

Hereinafter, the present invention will be described in detail with reference to Examples.
"Prescription 4 of fij'<! /r by conventional method (extrusion granulation)
To? , f is 0.8 buttφ granules.

Table 1 Comparative Example 1 Table 1, Granules of Formulation Example E 1 Fluidized Bed Coating Equipment 1
Polyvinyl acetal diethylaminoacetate (A 1v A ) (!: hydroxybropyrulose (I, )? JR combination 4h (A I8
A/II 1) (! (L) = 1/8),
The weight of granules! Coat the hole with 596,
Further II l) 1 costolytic coating at -65
096 Alms granules? 4j.

? P II 5.0, P 1
15.6.1) II 6.8 (Diurnal cycle @10th edition fA2
liquid), P117.6 (diurnal cycle 9th edition 2nd liquid), 1) I18
．． The results shown in Table 2 were obtained using a 10-station disintegration test method using a test solution containing 100% of benzicrane fumarate.

11-, Comparative Example 2 Table 11 Granules I of Formulation F Flow into Kg 11i11 Mfl
Granulate hydroxypropyl cellulose (1,) using a coating device iff.
Granules were obtained by applying 11,196 coats of 4+1 coach and f.

The obtained granules were subjected to the same dissolution test as in Comparative Example 1, and the results shown in Table 2 were obtained.

Comparative Example 8 Table 11 Prescription 1) l1ll'lwa1. I Kp style 1
Hydroxypropylcellulose (L) was coated using v1 layer coating device iM'x, and further I
Enteric coating was applied with IP-55 to obtain granules. A dissolution test was conducted on the granules prepared in the same manner as in Comparative Example 1, and the results shown in Table 2 were obtained.

Example 1 Table 11 Granules of formulation A were treated with polyvinyl acetal diethylamino acetate (AEA) using the above apparatus.
Hydroxypropyl cellulose (L) (7) mixture (A
The granules were coated with HA/HPO (L) = 1/8) at 5% based on the weight of the granules, and further enteric coated with HP-55 at 10% to obtain granules. A dissolution test was conducted on the obtained granules in the same manner as in Comparative Example 1, and the results shown in Table 2 were obtained. The results showed that the composition of the present invention was able to control the dissolution rate in each pH range very well compared to the control composition.

Example 2 Table 11 Granules 14 of Formulation B were prepared using the above apparatus to produce polyvinyl acetal diethylamino acetate (AEA) (!
:Hydroxyprobyl cellulose (L) (7) mixture (
AEA/HPO (Ll=1/4) was coated at 5% based on the weight of the granules, and a bath-based coating was applied to 1096 hlll, I/i'J'I.
I finished J1°l. Comparative Example 1
A dissolution test was carried out in the same manner as above, and the results shown in Table 2 were obtained.

The results showed that the composition of the present invention significantly controlled the bathing rate in the 11th period compared to the control composition.

Example 8 Table 1. The above device I'1 was applied to the condyles of prescription 0) f, I Kp.
diethylaminoacetate-1-(A I4 A
) and Hydroxypro211Lulose (L) Mixture 4
Of course (t\lj A/IIPO (1,) = 1/8) is the weight of the granules h! 596 coating and further II
I) -55 enteric coating 1096,
Condyles, l/ were obtained. A dissolution test of 4yl granules was performed on 1 person.
The same procedure as in case 1 was carried out, and the results shown in Table 2 were obtained. The results showed that the composition of the present invention had a lower performance than the control composition.
It was shown that the dissolution rate in the two regions was very well controlled.

Example 4 Mixing of diethylaminoacetate-1-(AI>A,) and hydroxypropyl cellulose (L) II (A E
A/HPO(L)=1/2) at 5% based on the weight of the granules.
After coating, a 10% enteric coating of HP-55 was applied to obtain granules. The obtained granules were subjected to a dissolution test in the same manner as in Comparative Example 1, and the results shown in Table 2 were obtained.

The results show that the composition of the present invention has a
It was shown that the elution rate in the HfD4 region was very well regulated.

Claims (1)

[Claims] +l) Sucrose fatty acid esters of all types h1. Japanese grains or tablets containing 2W/w 96 to 50 W/w%^11 are repeatedly coated with a water-insoluble compound or a mixture of a gastric-soluble polymeric substance and a water-soluble polymeric substance, and then coated with an enteric-coated polymer. (A composition made by combining W with 7iDi. The formulation IJt composition according to claim 1, which is an ether methacrylate]-methacrylic acid ester copolymer. (3) The water-soluble polymeric substance is a cellulose ether derivative rod,
Denbu A, vj# which is a visit isomer or a hinyl derivative! F
B? (i) Scope of water The pharmaceutical composition of Item 1, Item 11 (5). (4) The ratio of the water-bathable polymeric substance to the water-insoluble +1 or stomach-soluble polymeric substance is 0.25 to 1. Claim 1 '1Sl'il1 composition as described in the section. (5) IILB of sucrose fatty acid ester is 2~
16, particularly the pharmaceutical composition according to claim i411. (6) The present insoluble 4'l or gastric acetate 1-1 polymer-J'11 is a polyhinyl acetal diethylamino acid. 11 composition. (7) The water bathing polymeric substance is hydroxypropyl cellulose.Claim 4. The W11 composition described above. (8) Water turbine ta 41 or ampholytic polymer Vi
is polyhinyl acecool diethylamino acetate i
The pharmaceutical composition according to item 1 of the present invention, which is a water fd 4'l polymeric material or hydroxypropylcellulose.