JPS604124A - Quick dissoluble homogeneous drug composition and manufacture thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION The present invention relates generally to pharmaceutical compositions, and more particularly to pharmaceutical compositions with rapid solubility and enhanced biological effectiveness of drugs having low water solubility. related to things. The formulation also has good uniformity of drug content.

Many useful drugs have a water solubility of less than about 1 part by weight per 100 parts by weight of water (1o, o o omcg/ml) at a temperature of 25°C, and this depends on the absorption and biological properties of the drug. This can lead to poor effectiveness. Many of these drugs are used in small doses (less than sol+v).

Thus, it is difficult to obtain good uniformity of drug content, especially in tablet forms made by dry blending or direct compression.

The urinary and antihypertensive agent metolazone is a sulfonamide derivative, the chemical name of which is 2-methyl-5-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone. It is. This material is described in U.S. Pat. No. 3,3 (So, 518);
It has a water solubility of about 6 CL 3 mcg/tut at 5°C and 1 oo, omcg/- at 36°C. The problems associated with metolazone dosage forms are due to its poor decomposition properties, which are also due to poor water solubility. Burge
r etc., Drug Research, 25.24
(1975), n-butanol, water and Q, 01N
The specific dissolution rates of five different solid forms of metolazone in hydrochloric acid are reported. The amorphous metastable form of metolazone with a softening temperature of 140-155°C was observed to dissolve in 0.01 N hydrochloric acid about 8 times faster than the stable form with a softening temperature of 140-270°C. The lack of consistency involved in their preparation and the metastability of the polymorphs, which are still higher in solubility, make them unsuitable for practical use. Therefore, a stable dosage form of metolazone or other drugs with low water solubility, which exhibits improved degradation characteristics and good uniformity of the drug, and which is easily manufactured is desirable. This is because one would expect this to increase the biological effectiveness of the drug. The higher the biological efficacy, the lower the amount of drug required and therefore the side effects such as hypokalemia caused by the use of metallosin may be reduced. However, the inventor
Dispensing compositions of drugs that are difficult to agglomerate, exhibit significantly enhanced dissolution rates, and can be easily manufactured to provide good uniformity of the drug, especially in compositions with a drug content of less than 50 μl. discovered a pharmaceutical composition.

This improved effect is achieved by using a specific mixture of excipients and by placing the drug in particulate form.

SUMMARY OF THE INVENTION In accordance with the present invention, the majority of the particles are approximately 155μ in diameter.
A fast dissolving pharmaceutical composition of a low solubility drug is provided which is made from a dry mixture of a drug, microcrystalline cellulose and starch having a particle size distribution of less than 100 μm, preferably less than about 100 μm. When the preparation is a compressed tablet, unground or coarsely ground calcium phosphate and a lubricant are added to the mixture.

Alternatively, the drug may be ground and then mixed with starch, fine cellulose, unground or coarsely ground dibasic calcium phosphate, and a lubricant to form a free-flowing homo-dry mixture; A method of forming a fast dissolving tablet containing a low solubility drug composition is provided comprising compressing a mixture to form a tablet.

DETAILED DESCRIPTION The present invention is suitable for drugs with low solubility in water, especially those with little solubility (SS) (1 part by weight in 100-1000 parts of water at 25°C, and those with very little solubility (VSS). (
1 part by weight in 1000-10,000 parts by weight of water at 25°C)
or virtually insoluble (, P I ) (2 s °C water 1
(less than 1 part by weight per 0,000 parts by weight). Note that such drugs are referred to herein as "low-solubility drugs."

Many diuretics have a solubility of less than 1 part by weight in 100 parts by weight of water at 25°C, as shown below: SS, VSS
PI amiloride ethacrine Bendrofluazide bumethamide Methylclothiazide Benzthiazide butadiazide Metazolamide Chlorthalidone canrenone Kinetazone Cyclothiazide tetravamide Triamterene Evitiazide trichlormethiazide Furosemide hydroflumethiazide Hydrochlorthiazide meptidide Metolazone paraflutidide poly Thiazidoxipamide Other drugs with low water solubility include, for example: methaqualone, tartrate, chlorpromazine, atropine, codin, norethindrone acetate, phenobarbital, indomethacin, doxepin, acetohexa mido, cyfrizine, cilcidine hydrochloride, diazepam, reserpine, acetyldigitoxin, betamethasone,
Bisacodyl, cephalochrycin, chloramfenicoflu, chlortrianisene, erysmomycin estrate, griseofulvin, oxazepam, quinidine sulfate, cortisone acetate, digitoxin, disulfiram, erythromycin, estradiol, methyl 7”L/donisolone, valamethasone acetate, pargyline hydrochloride, gledoninrone, primidone, simethicone, sulfisoxazole,
Testolactone and Testosterone.

Many of the drugs listed above are generally used in dosages less than 50 μl. The increased dissolution rate of the compositions of the present invention allows for lower dosages per tablet or capsule. As single drug doses become smaller, it becomes increasingly difficult to achieve uniformity of the drug contained in the preparation.

The compositions of the present invention have been found to have improved uniformity in dosage even when the drug content is less than 1η.

The high melting point (267-270°C), single crystalline stable form of metolazone made by the method described in U.S. Pat. No. 3,360,518 has the following particle size distribution: 615% 50% 84% 460 μm 190 μm 83 μm2.5 where d is the particle diameter (μm) in percent of the indicated weight and amount, and σg is the geometric standard deviation.

The water solubility of single crystalline metolazone at 25°C is approximately 6 om.
cg/-. To provide increased solubility and better uniformity of the drug in compressed tablet or capsule dosage forms, metolazone or other drugs can be prepared, for example, by Fitzpatrick fitted with a ÷1 sieve (sieve mesh o, o33 in).
Mill or Su 346o herringbone sieve (sieve mesh o, o1st
Finely grind in a grinding mill such as a Mikropulverizer fitted with n).

In the latter case, smaller preferred particles (less than about 100 μm 8
4% by weight) is obtained. Single doses of metolazone or other drugs generally range from about 0.05 to 10% by weight.

The excipient is selected to be compatible with the drug, so that it provides good flow properties (if a tablet is desired) for the tablet.
This results in a formulation mixture that exhibits a free-flowing consistency, yet eliminates the tendency for non-mixing so that the drug content between tablets does not vary. Excipients are also selected to provide enhanced solubility properties to the drug and therefore better surface drug efficacy.

Excipients include, but are not limited to, fine quality cellulose and dibasic calcium phosphate as a diluent.

Fine quality cellulose also acts as a filler and disintegrant.

The particle size distribution of a typical commercially available cellulose abrasive is as follows: 616% 50% 84% d d 77 μm 44 μm 25 μm t 74 (where d = diameter, σg = geometric standard deviation) The amount of quality cellulose ranges from about 10 to 90% by weight, preferably about 40 to 50% by weight.

Dibasic calcium phosphate is used to improve the flow properties of the formulated mixture to enable direct compression of the mixture into tablets. The particle size distribution of a typical unpulverized commercially available calcium phosphate material is as follows: 616% 50chi 84% d d σg 225 μm 140 μm 88 μm 163 The inventors have discovered that by coarsely crushing calcium phosphate, It has been found that the uniformity of drug concentration in compressed tablets is improved. This coarse grinding appears to eliminate the non-mixing tendency that has been noticed when flow-enhancing excipients are used in other systems.

Fitz with +000 sieve (sieve mesh αo2otn) installed
A typical particle size distribution obtained from coarse grinding at high speed with impact forward with a Patrick grinding mill was as follows: d d σg d16chi 5 (1% 84% 170 μm 9Bfim 44 μm 133 Composition The amount of dibasic calcium phosphate therein ranges from 10 to 90% by weight, preferably from 35 to 50% by weight.

Starch is added to the formulation mixture to improve disintegration or dissolution of the composition. Also, fatty acids or fatty acid salts such as magnesium stearate are added as lubricants to improve the flow of the formulation mixture during manufacture.

The amount of starch in the composition typically ranges from about 1 to 20% by weight, and the amount of lubricant ranges from about Q, 1 to 50% by weight.

K dye can be added for identification.

Typical tablet weights range from about 50 to 40,019.

The invention is further illustrated by, but is not limited to, the following examples. In addition, in the examples, materials and tablets were evaluated using the following method.

Particle Size Distribution: Particle size distribution of drug and excipients was determined by sieve analysis technique. A11en Bradley 5
Five grams of each test material was placed on the top sieve of a six-set American standard sieve in the onicSifter. The sieves were shaken for 15 minutes. The sieve that can be used is 80 mesh (180 μm), 1
00 mesh (150 μm), 140 mesh (106
micrometer), 200 mesh (75 micrometer), 270 mesh (53 micrometer), and 400 mesh (58 micrometer). A weight fraction retained on the sieve was obtained. Specific weight% (16
, 5o and 84), the particle size (d) in Edmun
son Advances in Pharmaceut
ical 5sciences (editor BeanSH,
Obtained from the log globality plot of the data described in S. et al., London, UK, Academic, 1967, p. 95). Such particle sizes are designated as d16 d5o and d84.

The geometric standard deviation (σg) was determined by calculating the line slope from the plot.

Tablet weight: Weigh at least 10 tablets individually and from these values calculate the average and standard deviation of the tablet weight.

Tablet Thickness: Thickness values of at least 10 tablets were measured with an Ames thickness gauge and the average of the values calculated.

Hardness Size 2 Hardness values of at least 10 tablets
The hardness was measured using a hardness tester, and the average and standard deviation of the obtained values were calculated.

Friability: Ten tablets were weighed before and after 10 minutes of being run through the Roche mill, and the difference was expressed as friability.

Dissolve 6 tablets of IIs2 in 37°C ty) H water (US
USP disintegration device (U, S, Pha
rmacopia.

revision XX, p 95 B),
The time required for all tablets to pass through the sieve of the basket device was recorded.

The content was analyzed individually by HPLC method and these values were then expressed as a percentage (%) of the theoretical content. The mean and standard deviation of such values were obtained.

It was essentially the same as that shown as Apparatus 1 in USP XX, p 959. The details of the equipment and melting conditions are as follows: 1 container (Kimble glass number 55700, height 1
Hydrochloric acid solution (o, I
N) 1000d was added. The dissolution medium was maintained at 67°C±0.5°C by immersing the container in a suitable water bath.

Six such containers were installed, and the dissolution medium in the containers was
The mixture was stirred with a Model 616 stainless steel basket-type stirrer driven at 50 rpm by a multi-shaft drive. One tablet was placed in each basket stirrer, and all baskets were simultaneously lowered into the dissolution medium at the beginning of dissolution. The dissolution medium was filtered through a filtration device equipped with a small plug into a glass tube, from which it was pumped through a polyethylene tube into the cell in a flow path 1 cIn and back into the dissolution vessel.

A Master Flex pump drive was used for this purpose. The flow rate in each cell was kept at approximately 16 td/min.

B e c km with multi-channel chart recorder
235 nm for metolazone or 51 nm for triamterene using an an model 25 or 35 spectrophotometer.
The absorbance change of the sample as a function of time was monitored at 0 nm. Metolazone or triamterene standards were similarly tested and sample concentrations were calculated.

Example 1 150,000 tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Metolazone, fine quality uOη 575.0017 Magnesium stearate 130■ 195.00g total 1
30.00η 19,50αno 1 Procedure: t Chemical starch and 150 mouths of starch were passed through a Φ30 mesh stainless steel copper sieve.

2 The two starches from step 1 above were mixed in a "double cone" blender for 10 minutes.

Mounted on Mikropulverizer 346
0H, B.

Metolazone was passed through a sieve (sieve mesh o, o1ain).

3. In the modified starch/starch 1500 mixture from the second step, an equicomparative dilution of the metolazone to be ground was carried out.

t ooo sieve (sieve mesh n, o2otn) r attached
Unground calcium phosphate was passed through a Fitzmill J and subjected to high speed processing with shock forward.

5. The ground calcium phosphate and fine quality cellulose from step 4 were mixed in a suitably sized Lodige mixer for 5 minutes.

& The equal numerical dilution from step 3 was added to that of step 5 and mixed for an additional 15 minutes.

l Magnesium stearate was passed through a ≠30 mesh stainless steel sieve to which a small portion of the blend from step 6 was mixed. This was added to the blend residue and mixed for 15 minutes.

8. 13011 using 3Ajn standard concave tool
v Tablets were compression molded.

The data obtained are shown in the following table: Friability: Q, 6% Disintegration: 15 sec The particle size distribution of metolazone to be crushed is as follows: d d 0g d16 50 84 94 μm 56 μm 34 μm 173 Example 2 Tablets s, o o o tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Metolazone, microcrystalline 100η s, oog magnesium stearate 4.00ql 2α00g total 40[
LOOKI 2,000.001 Procedure: t Pass the modified starch and starch 1500 through a ≠60 mesh stainless steel sieve.

2 The starch two glazes from step 1 above were mixed in a "double cone" blender for 10 minutes.

3. Φ3 installed on Mikropulverizer
Metrason was passed through a 460H, B sieve (U mesh o, o15 inch). The particle size distribution was as described in Example 1.

4. A geometric dilution of the metolazone to be ground was carried out in the modified starch/starch 1500 mixture from the second step.

5. The fine quality cellulose and unground Cal/Rum phosphate were mixed in a suitable "double cone" mixer for 5 minutes.

& The equal numerical dilution from step 4 was added to that of step 5 and mixed for an additional 15 minutes.

The magnesium stearate was passed through a 60 mesh stainless steel sieve and mixed with a small portion of the blend from step 6. This was added to the blend residue and mixed for t5 minutes.

8, 40011 using 3/8 in plane bevel tool
v Tablets were compression molded.

The data obtained are shown in the following table: Disintegration @: 15 sec Example 3 5,000 tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Metolazone, microcrystalline tooηs, oog magnesium stearate 4.00wq 2α00g total 400
．． 00η 2.00αooy Procedure: t Pass the chemical starch and starch f#1500 through a 30 mesh stainless steel screen.

Z The two starches from step 1 above were mixed in a "double cone" blender for 10 minutes.

3, + 1 i'kli (f!i11 eyes o, o33
The metolazone was passed through a Fitzmill J equipped with a 1000 ml (in) and subjected to high speed processing with shock forwarding.

4 A geometric dilution of the metolazone to be ground was carried out in the modified starch/starch 150G mixture from the second step.

5. Fine quality cellulose and unground Calciramula phosphate were mixed appropriately in a "double cone" mixer for 5 minutes.

6. Add the equal numerical dilution from step 4 to that of step 5 and mix for an additional 15 minutes.

l Magnesium stearate was passed through a Φ30 mesh stainless steel sieve into which a small portion of the blend from step 6 was mixed. This was added to the blend residue and mixed for 15 minutes.

400η tablets were compression molded using an 8,3/8 in flat beveled tool.

The data obtained are shown in the following table: Disintegration: 10 sec Compared to Example 2, the slightly lower dissolved Nl rate and the higher variation in drug content uniformity indicate that pulverization of metolazone is preferable. . The particle size distribution of metolazone to be pulverized is as follows: 2416% 50 cm 84 cm d d σg 155 μm 86 μm 48 μm '-9 Example 4 Metolazone (0.5■) Tablets Tablets with the following composition 5. 00 pieces were prepared. A direct compression method was used for the tablet compound.

Metolazone, microcrystalline 5i 0.50 mg 2.50 j
i Calcium mystearate 4.00 vq 2 (1
009 total 400.00■ 2,00a009 moves j10
: T Chemical starch and starch 1500 were passed through a 30 mesh stainless copper sieve.

2. The two starches from step 1 above were blended in a "double cone" blender for 100 minutes.

3. Install it on the Mikropulverizer +
Metolazone was passed through a 3460H, B sieve (sieve mesh α013 inch). The particle size distribution was as described in Example 1.

4. Equicomparative numerical analysis of milled metolazone was carried out in the modified starch/starch 1500 mixture from the second step.

5. QOO-sieve (sieve mesh o, o2o; n) r attached
Fitzrnill J unground calcium phosphate was passed through high speed processing with shock forward.

6. The fine quality cellulose and unground calcium phosphate were mixed in a suitable "double cone" mixer for 5 minutes.

l The equal numerical dilution from Step 4 was added to that of Step B and mixed for an additional 155 minutes.

8. The magnesium stearate was passed through a 30 mesh stainless steel sieve and mixed with a small portion of the blend from step 7. This was added to the blend residue and mixed for 155 minutes.

9.400 tablets were compression molded using a 578 inch flat bevel tool.

The data obtained are shown in the table below.

45.6 58.9 7Q, 3 79.0 B2.7 Friability: 0.4% Disintegration: 15 sec Regarding the tablets prepared when the method of Example 4 was carried out without crushing the metolazone or calcium phosphate. The following data were obtained: 13.0 19.7 29.5 5B, 9 45.5 Friability: 0.28 Chi Disintegration: 10 sec Such tablets were not accepted due to low dissolution rate and poor homogeneity assay. Not done.

When metolazone was micronized as in step 3 of Example 4, the resulting tablets were tested for drug content assay 9.
4.5±6, improved with 68.0% metolazone dissolution from the tablets.

Calcium phosphate is completely extracted from fine quality cellulose (40011
1P tablets), fluidity problems arose and the tablets became hard. This was also done for the 3101+v tablet, and although flow and solubility were satisfactory, the drug content assay was 10B±6.0H. Omitting both calcium phosphate and starch resulted in poor dissolution of metolazone (348% in 1 hour).

Example 5 Metolazone (0.5■) Tablets 10,000 tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Metolazone, microcrystalline 0.50 5.009 Magnesium stearate 1.50η 15.00p total 15
[LOOη 1,50 [LOOf1 Procedure: t The modified starch and starch 1500 were passed through a 30 mesh stainless copper sieve.

2. The two starches from step 1 above were mixed in a "double cone" blender for 10 minutes.

3. Installed on Mikropulverizer 5
Passed through a 460H, B sieve (sieve mesh o, o1stn) K metolazone.

4 Equicomparative dilutions of metolazone to be ground were made in the modified starch/starch 1500 mixture from the second step.

5.000 sieve (sieve mesh 0.020 inch) r
Unground calcium phosphate was passed through a Fitzmtll J and subjected to high speed processing with shock forward.

& Mill the calcium phosphate and fine quality cellulose from step 5 in a suitable "double cone" mixer.
Mixed for a minute.

l The equal numerical dilution from Step 4 was added to that from Step 6 and mixed for an additional 15 minutes.

& Magnesium stearate was passed through a 60 mesh stainless steel sieve to which was mixed a small portion of the blend from step 7. This was added to the blend residue and mixed for 15 minutes.

9.%in 150 square tablets were compression molded using standard concave tools.

The data obtained are shown in the table below.

Friability: α0 Collapse: 15 sec Example 6 Example 5 was repeated using the following formulation. Batch size is 1! l
0IIIF tablets were 10,000 and 150,000.

Metolazone, Shoka 0. so q5.009 magnesium stearate t3omy 13. oo fl total 11.00■ 1,30α00g 1Q, in a batch of QOO tablets, the variation in tablet weight is 130±
The uniformity of drug content was 9'14±t8, and the metolazone dissolution after 1 hour was 7D, 2.

For a batch of 150,000 tablets, the tablet weight variation was 129±1
9η, drug content 105±5, metolazone dissolution after 5.1 hours was 73.4%.

Example 7 So, o o o tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Metolazone, fine quality 0.25■ 12.5II steari>1 magnesium 4.00 W 20100g total
400.00 ■ 20,000,001 hands: t Chemical starch and starch 1500 were passed through a ÷30 mesh stainless steel sieve.

2. The two starches from step 1 above were mixed in a "double cone" blender for 10 minutes.

! , mounted on the Mikropulverizer 3
Metolazone was passed through a 460H, B sieve (sieve mesh o, o13 inch). The particle size distribution is as described in Example 1.

4 Equicomparative dilutions of metolazone to be ground were made in the modified starch/starch 1500 mixture from the second step.

s, ooo sieve (WM eye o, o2oin) was installed [
Unground calcium phosphate was passed through a F"itzmill J and subjected to high speed processing with shock forwarding.

& Add the pulverized calcium phosphate and fine quality cellulose from step 5 to a suitable lodige mixer? - Mixed for 5 minutes.

l The equal numerical dilution from Step 4 was added to that from Step 6 and mixed for an additional 15 minutes.

8. The magnesium stearate was passed through a 30 mesh stainless steel sieve and mixed with a small portion of the blend from step 6. This was added to the blend residue and mixed for 15 minutes.

400η tablets were compression molded using a 9, 3/8 inch flat bevel tool.

The data obtained are shown in the table below.

Disintegration: 15 sec As demonstrated in the above examples, a free-flowing, directly compressible homogeneous formulation of metolazone is obtained by including in the formulation a mixture of fine quality cellulose and coarsely ground calcium phosphate. Either of these two excipients alone does not provide the desired properties of good flow, rapid dissolution and drug uniformity. Thus, milling of calcium phosphate improved the uniformity of metolazone concentration in the tablets.

Example 8 20,000 tablets having the following composition were prepared. A direct compression method was used for the tablet compound.

Triamterene 50.00 nl 100D 9 Modified starch 1600-620g Magnesium stearate 2. OO~ 4Qg total 4
00.00η 5ooo g Triamterene had the following particle size.

616% d 50 chi d 84 chia 6 μm 41 μm 17 μm Procedure t Microcrystalline cellulose and unground dibasic calcium phosphate were mixed in a suitable planter for 5 minutes.

2. Triamtele/mixture from step 1 100ONK
Mix in a suitable planter for 5 minutes and then mix the same mixture for an additional 2000. li+ was added and mixed for 5 minutes, then the remaining portion of the mixture from step 1 was added again and mixed for 5 minutes.

3. Starches were mixed for 5 minutes.

4. To this starch mixture, added the mixture from step 2 in three increments (isoog, 2500 g, remainder) and mixed for 5 minutes after each addition.

5. Pass the magnesium stearate through a 60 mesh stainless steel sieve and add to the mixture from step 4 and mix for 2 minutes.

400 wv tablets were compression molded using a 6, 3/8 inch flat beveled tool.

The obtained takes are shown in the table below.

Collapse: 22-5sec 28,3 44.5 710
As can be seen from the foregoing description, the present invention provides rapid dissolving drug compositions of varying particle sizes and doses that are easily manufactured into tablets by direct compression with uniform drug content (variation less than ±4 inches). bring.

Rapidly dissolving capsule dosage forms can also be produced. Such effects are achieved by specific excipient mixtures and, if necessary, by micronization of the drug so that it is provided in finely divided form.

Fine particle size was found to be essential for rapid drug dissolution and uniformity of drug dosage.

Claims (9)

[Claims] (1) A rapidly dissolving pharmaceutical composition made from a dry mixture of a low solubility drug, fine quality cellulose, and starch having a particle size distribution in which the majority of the particles are less than about 155 μm in diameter. 2. The composition of claim 1, wherein the mixture contains about 0.05 to 50 weight percent of fine cellulose and about 1 to 20 weight percent of starch. (3) The composition of claim 1, wherein the mixture comprises dibasic calcium phosphate. 4. The composition of claim 3, wherein the mixture contains about 10 to 90% by weight of unground or coarsely ground dibasic calcium phosphate. (5) A composition according to claim 1, wherein the mixture is characterized by about 0.1 to 50 wt. lubricant. (6) The composition according to claim 1, which is in the form of a pressed tablet. (7) The composition according to claim 1, wherein the drug is triamterene. (8) The composition of claim 1 characterized by a particle size distribution in which the majority of the particles are less than about 100 μm in diameter. 9. The composition of claim 1, wherein the drug has a water solubility of about 1 part by weight or less per 100 parts by weight of water at a temperature of about 25°C. Mixing the drug with starch, fine-quality cellulose, unground or coarsely ground dibasic calcium phosphate, and a lubricant to form a free-flowing homogeneous dry mixture;
A method of forming a rapidly dissolving tablet containing a low solubility drug composition comprising then compressing the mixture to form a tablet. 11. The method of claim 10, wherein the drug is pulverized so that the majority of the drug particles are less than about 155 μm in diameter.