JPS6242918A - Sustained release pharmaceutical - Google Patents

Abstract

PURPOSE:To economically obtain a sustained release pharmaceutical capable of surely controlling the elution of a drug without any influence of tableting pressure or hardness, by adding a water-soluble high polymer and a disintegrating agent which is another elution regulator to the drug and uniformly dispersing both components therein. CONSTITUTION:A sustained release pharmaceutical obtained by uniformly dispersing a water-soluble high polymer, e.g. hydroxypropyl methyl cellulose, polyvinylpyrrolidone (PVP) or polyvinyl alcohol (PVA), drug and a disintegrating agent, e.g. a mixture of microcrystalline cellulose with sodium carboxymethyl cellulose (CMC-Na), starch or CMC, therein and tableting the resultant mixture by a well-known method. Since a great variation in elution due to the little difference in amount of the water-soluble high polymer can be controlled by a controlling factor for accelerating the elution by the disintegrating agent which is another elution regulator, the elution of the drug can be surely controlled. Thereby, the aimed sustained release pharmaceutical can be simply and economically obtained.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to depot formulations.

(Problems to be solved by conventional techniques/inventions) Long-acting preparations, long-lasting drugs, drugs 11. Various studies have been conducted to maintain the efficacy without reducing the number of administrations (1) or to not increase the +fit +i concentration more than necessary, that is, to reduce side effects. However, with the so-called coating method and melt granulation method, which have been carried out in the past, there are large variations in the drug release characteristics between the two and one batch, and there is also a technical and economical problem. I was not satisfied either. For example, there are coating methods that are p+-1 dependent or independent; ■) II-dependent coating methods are difficult to apply to patients with achlorhydria, and furthermore, the thickness of the film It is extremely difficult to uniformly apply the powder to all granules or tablets Δ11 without pinholes. Regarding the melt granulation method, the amount released varies depending on the particle size distribution, and the amount released is also significantly affected by the size, pressure, and hardness of the tablet. In order to solve the shortcomings of the long-acting preparations described in Section 1-1, various tests have been carried out. There are sex preparations. However, the former is limited to covering jl' (17.4
It is a formulation prepared by the broad definition:]-Tinta method containing a dissolution regulator. Therefore, the subject rlJ! +' (coalescence is elution θ
) has the disadvantage that it remains in the body.
Goro (911) is a formulation in which drug release is controlled by the addition and type of water-soluble polymer, as well as by a special manufacturing method, control method using only water-soluble polymer 111, tablet compression pressure, Disadvantages include that the amount of drug released differs depending on the hardness, and that it is uneconomical due to the special manufacturing method. In view of the current situation, the present invention t1 et al. has developed an elution modifier that can be dissolved in water without using a coating polymer, without relying only on water-soluble A''noi molecules, and without requiring a special manufacturing method. By adding a disintegrant, which is another dissolution control agent to the polymer, the dissolution of the drug can be reliably controlled, and all that is required is a normal mixing operation (for example, using a type mixer or vertical mixer). The present invention was completed by easily and economically producing a long-lasting preparation and producing 41 scales.

(Means for Solving the Problem) The water-soluble polymer of the present invention is a water-soluble substance that has the effect of delaying the elution of a drug and is soluble in water regardless of p I-1. In more detail, hydroxypropyl methylcellulose (hereinafter referred to as T (PMC)), polyvinylpyrrolidone (hereinafter referred to as PVP), polyvinyl alcohol (hereinafter referred to as PVA), hydroxypropyl cellulose (hereinafter referred to as [-1PC) ) or methyl cellulose (hereinafter referred to as MC).

By uniformly mixing the leakage-resistant water-soluble polymer and the medicine, the durability is 1 daf! However, when water-soluble polymers are added in small quantities, the dissolution rate varies widely due to slight differences in the addition site, differences in operation, and hardness of the tablets or granules, resulting in poor reproducibility. These words include, for example, flurbiprofen (hereinafter referred to as FP), a non-pyrine anti-inflammatory analgesic, as a medicine, and 1-TPM as a water-soluble polymer.
Table 7 and FIG. 7 show the results of examining the 1-hour drug dissolution rate using C as an example. However, the dissolution test is based on the disintegration test method of the 10th edition of the Japanese Pharmacopoeia (hereinafter referred to as 10), and the maximum absorption wavelength of t' p is 248 nm.
A: Determined from absorbance m'' in J-9 near l.

Table 7 Dispersant: Low-substituted hydroxypropylcellulose, that is, 40% (wt%, same hereinafter) of water-soluble polymer based on the amount of drug/dispersant 1) By using a water-soluble polymer, the elution of the drug can be controlled. However, at 40%, the elution rate is 53%.
, at 30%, the elution rate is 80% -) There is a pulley and a slight amount of water solubility ('1-. It is clear that there is a large variation in elution due to differences in polymer stars.

Therefore, by adding another dissolution regulator, a disintegrant, this becomes a control factor that speeds up the dissolution, and the dissolution of the drug can be reliably controlled. For example, as shown in Figure 7, by using a water-soluble polymer that accounts for 60% or more of the pharmaceutical preparation 11Q, a slight difference in water-soluble polymer I can be prevented from affecting the dissolution rate. By subsequently adding a disintegrant, the dissolution rate could be freely controlled without affecting the hardness of the tablets and granules. In other words, instead of controlling only the straight line part with a large slope shown in FIG. 7, the part with a small slope is used to control that one novel with a disintegrant. What is the disintegrant of the present invention?
When used in medicine, substances that are not harmful to living organisms, such as a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (hereinafter referred to as Avicel RC; manufactured by Asahi Kasei Corporation), starch, carboxymethyl cellulose starch derivative bitroxypropyl star y- or Sucrose fatty acid esters, etc.1'').In addition, since the long-acting preparation of the present invention uniformly mixes the drug with a water-soluble polymer and a disintegrant,
Pharmaceuticals, such as antiallergic agents 8-hexyloxy-
3-(Il+-te1-razol-5-yl)-20-chromen-2-one (hereinafter referred to as A L-136) (Japanese Patent Application Laid-open No. 5-7687: (see publication number)
Flurbiprofen, ibuprofen, a non-pyrine anti-inflammatory analgesic, and befunolol hydrochloride, a β-blocker agent (see Japanese Patent Publication No. 1983-20063), should be gradually dissolved in 10 parts I liquid to the outer periphery of the core or J≧. Furthermore, since no coating polymer is used, it does not have the disadvantages that occur when dissolving conventional long-acting preparations, such as leaving a shell or leaving granular particles even after dissolution.

To produce the long-acting preparation of the present invention, 5% to 200%, preferably 10% to 150% of the amount of the drug/dispersant is a water-soluble polymer, a drug/dispersant J: a water-soluble polymer, and a water-soluble polymer. Polymer - Add a disintegrant of 10% to 200%, -7 = preferably 20% to 100% for the eyes, and further add excipients and lubricants as necessary, mix uniformly, Compress the tablets using the following method.

In addition, 5% to 200% of the pharmaceutical star, preferably,
Add 10% to 120% of a water-soluble polymer, or 0.1% to 200%, preferably 1.0% to 100%, of a disintegrant to the pharmaceutical and water-soluble polymer weight, mix uniformly, and prepare a known Multi-layered tablets or hard-coated tablets made by adding a lubricant if necessary and mixing them uniformly using special equipment. Compress the tablets by known methods and equipment without making them into locks.

As shown above, the formulation technology of the present invention is no different from conventional methods, and since the process is extremely simple, there is no need for work standards with special precautions or special equipment, and it is easy to use. It is easy to operate and economical.

In general, in long-acting preparations, especially in tablet form,
No matter how precisely the focus is adjusted or the tablet compression pressure is adjusted, variations in thickness and hardness will occur, so it is difficult to prevent variations in the dissolution rate. . In line with this, the long-acting preparation of the present invention has no influence on tableting, hardness, size, etc. when it is made into tablets, and it is possible to freely control dissolution while being T3-pure by dedicating the process. It is something that can be done.

(Example) The present invention is not limited to such embodiments.

The elution test in the examples was carried out in accordance with the 10-station disintegration test, and the 10-station solution I or ■ solution was used as the eluent. In addition, the dissolution rate was determined by the absorbance at the maximum absorption wavelength of each drug [I]) using a spectrophotometer manufactured by Ikkotachi Seisakusho Co., Ltd.].

\,,- ゛ーーー−“−゛−′＼ Example 1 (Comparison! D(1)(2) FT) Raw powder 60 60
60 low substituted hydroxypropyl 25.7
25.7 25.7 Cellulose (hereinafter referred to as T)
I-(31 dosuru) 1 (PMC9051110051,
451,451,4 starch
0 27.4 54.8 Calcium stearate 3 3 3 A long-acting preparation was produced using the above ingredients and according to the method shown below. That is, FP bulk powder and L 1-T31. T-
In order to reduce the bulk of the mixture and improve fluidity, isopropyl alcohol was added to the mixture of TPM C and starch that was uniformly dispersed as a kneading liquid.
Granulate and dry. Furthermore, after uniformly mixing calcium stearate with the dried granules, 7.5 mmφ
Compress into tablets with a punch of ~8 mmφ. Table 1 and FIG. 1 show the dissolution rate of the drug from the three types of tablets obtained.

As is clear from Table 1 and FIG. 1, the addition of starch as a dissolution regulator increases the dissolution rate of the drug. Further, in the dissolution test, it was observed that the tablet gradually disintegrated from the outer periphery, and by the time dissolution was completed, all the tablets were completely dispersed in the eluate.

1＼, -1111゛〜・, 1 Example 2 FP bulk powder 60 60
60 60LT-13], 25
．． 7 25.7 25.7 25.7HPMCD
O81110068,668,668,668,6CM
CI5.4 30.9 46.3 61. ．． 7 Calcium stearate 3 3 3
3FP bulk powder and LH3], 1-I P MC and CM
Isopropyl alcohol is added as a kneading liquid to a mixture in which C is uniformly dispersed, and the mixture is kneaded, granulated, and dried. Furthermore, after calcium stearate is uniformly mixed into the dried granules, they are compressed into tablets using a punch of 8 mm to 8.5 mm.

The drug dissolution rates from the four types of tablets obtained are shown in Table 2 and Figure 2.

As is clear from Table 2 and FIG. 2, it can be seen that the dissolution rate of the drug increases as the amount of CMC, which is a dissolution regulator, increases. Further, in the dissolution test, it was observed that the tablet gradually disintegrated from the outer periphery, and by the time the dissolution was completed, all the tablets were completely dispersed in the eluate.

Example 3 AL-1,36 bulk powder 75 75 7
5 75Croscarmcl]ose Sodj
um 15 15 15 15HPM
C90S11100 36 45 54
63 Magnesium stearate 9 9
9 9(+) (2) (3)
('I) AL-1,36 original powder 75
75 75 75Croscal+ne
l 1ose 5odiu+n 15 1
5 15 15HPMC90511100
36455463 Abisse/l/'RC-5915054
5861 Magnesium stearate 9 9
9 9 Using the above ingredients, the tablets are manufactured in the same manner as in Example 1 and compressed with a punch of 7 mm to 8.5 mm.

Table 3 and FIG. 3 show the drug dissolution rates from the eight types of tablets obtained.

As is clear from Table 3 and FIG. 3, it was found that the addition of the dissolution regulator Avicel R, C-591 increased the dissolution rate of the drug, that is, the dissolution rate was accelerated. Further, in the dissolution test, it was observed that the tablet gradually disintegrated from the outer periphery, and by the time the dissolution was completed, all the tablets were completely dispersed in the eluate.

15-Example 4 The above ingredients were kneaded in the same manner as in Example 1, cylindrically granulated using a screen with a hole diameter of mmφ, and dried. get.

Table 4 and FIG. 4 show the drug elution rates from the two types of granules obtained.

As is clear from Table 4 and Figure 4, normal granules (2
), it can be seen that the long-lasting granules (1) according to the present invention reliably suppress the drug dissolution rate. Furthermore, in the dissolution test, it was observed that the granules gradually disintegrated, and by the time the dissolution was completed, they were all completely dispersed in the eluate.

Example 5 Easily soluble part (granules) A I, -136 bulk powder 40 parts Starch 40 Sustained release part (granules) (A) AT, -136 raw powder 40 parts HP MC C90S11 Ion 35 Sucrose fatty acid ester 5 (I3 ) A L-1,36 original 40 parts HP MC90511400035 Sucrose fatty acid ester 5-1-, the easily soluble part granules and sustained release part granules were manufactured by the manufacturing method of Example 1 and Example 4, respectively. , the blending ratio of the easily soluble part and the sustained release part was changed to 2:1.1:1 and I:2, and magnesium stearate A (9
mg/tablet) to obtain one 169 mg tablet.

Table 5 shows the dissolution rate of the drug from the six types of tablets obtained.
It is shown in FIG. 5-A and FIG. 5-B.

As is clear from Table 5 and Figures 5-A and B, by changing the blending ratio of the easily soluble part and sustained release part, that is, by increasing the blending ratio (vomit) of the easily soluble part, the dissolution rate of the drug increases. I know what's going on. This means that the desired dissolution amount can be obtained with tablets that are compressed using the same method and operation as when manufacturing regular tablets, and there is no need to use special equipment to formulate multilayer tablets or dry-coated tablets. It was confirmed that it was good. Furthermore, in the dissolution test, it was observed that the tablet gradually disintegrated from the outer periphery, and by the time dissolution was completed, all the tablets were completely dispersed in the eluate.

Example 6 Easily soluble part (granules) Fp bulk powder 30 parts Starch 30 Sustained release part (granules) (A) FT3 bulk powder 30 parts HPMC9
0S11100 27 (B) FP bulk powder 30 copies HP MC
90SH400027 The above-mentioned easily soluble part granules and sustained release part granules were manufactured by the manufacturing method of Example 1 and Example 4, respectively, and the blending ratio of the easily soluble part and sustained release part, that is, the addition rate (%) of the sustained release part 50%, 60
%, 70%, and 80%, and further added magnesium stearate (3 mg/tablet) to the mixture, and added 1 tablet to 1 tablet.
．． Obtain 23 mg tablets.

The dissolution rates of the eight types of formulations obtained are shown in Table 6, Section 6-A.
and Fig. 6-B.

As shown in Table 6 and Figures 6-A-B, it can be seen that the dissolution rate of the drug decreases as the addition sensitivity of the sustained release portion increases. This means that it is possible to obtain an initial dissolution effect even with tablets of ordinary formulations, and there is no need to make them into multilayer tablets or hard-coated tablets. It was confirmed that the elution dish could be freely controlled.

(Effects of the Invention) As described above, the long-acting formulation of the present invention differs from conventional formulations using coated polymers or formulations requiring special manufacturing methods, in that the long-acting formulation of the present invention does not require a water-soluble polymer as a dissolution regulator. Furthermore, by adding a disintegrant, which is another dissolution control agent, it is possible to control the dispersion of the dissolution group of the drug to a minimum without being affected by tableting pressure or hardness (in the case of tablets).

In addition, long-lasting preparations can be produced simply and economically by just the usual mixing operation.

[Brief explanation of drawings]

Figures 1 to 6A j3 and Figures 6-B are Examples 1 to 6, respectively.
A graph showing the results of a dissolution test of the obtained long-acting formulation,
FIG. 7 is a graph showing the relationship between water-soluble polymer weight and elution rate.

Claims (1)

[Scope of Claims] 1. A long-lasting preparation characterized by uniformly dispersing a water-soluble polymer, a drug, and a disintegrant. 2. The long-acting preparation according to claim 1, wherein the water-soluble polymer is hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, or methylcellulose. 3. The sustained-release preparation according to claim 1 or 2, wherein the disintegrant is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, starch, carboxymethyl cellulose, hydroxypropyl starch of a starch derivative, or sucrose fatty acid ester. 4. The long-acting preparation according to claim 1, comprising a sustained release part in which a water-soluble polymer, a drug, and a disintegrant are uniformly dispersed, and an easily soluble part made of a conventional drug. 5. The long-acting preparation according to claim 4, wherein the water-soluble polymer is hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, or methylcellulose. 6. The sustained-release preparation according to claim 4 or 5, wherein the disintegrant is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, starch, carboxymethyl cellulose, hydroxypropyl starch, a starch derivative, or sucrose fatty acid ester.