TW533082B - Tetrahydrolipstatin containing compositions - Google Patents

Abstract

Product containing tetrahydrolipstatin as the active ingredient and pharmaceutically acceptable excipients, characterized in that it is in the form of particles with a diameter of 0.25 to 2 mm; and pharmaceutical preparations or compositions for oral administration containing the product.

Description

> 33082 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (1) Tetrahydroribastatin (THL) is an inhibitor of pancreatic lipid anti-enzyme, and it is generally referred to as kuai Lisitie Special (orlistat). When THL is used for medicine, it is particularly used as an anti-obesity agent, and a pharmaceutical composition containing THL as an active agent is described in US Patent No. 4,598,089. Since its about 44. (: Low melting point, THL undergoes hydrolysis and thermal degradation, especially when stored in moist air or 35. (: above dry air. Further, the traditional dosage form described in US Patent No. 4,598,089 Such as tablets or hard capsules, when the tablets are compressed or encapsulated, it is not easy to mix with powder mixing method or traditional wet granulation method due to the impregnation and adhesion phenomenon. Therefore, THL < production and dosage forms need to be prepared and stored. It is stable against humidity and heat from one point of view. In one aspect, the present invention is related to-products containing THL, stabilizers and pharmaceutically acceptable excipients as active ingredients, which are characterized by a straightforward handling of 0 · 2 5 to 2 mm granules. ~ These granules are usually granules or pellets. The preferred pellets require the presence of microcrystalline cellulose. The diameter of the preferred pellets ranges from about 0.05 to about 15 mm. 'THL-containing particles do not exhibit the phenomenon of adhesion and immersion, and show better stability of THL. This fx Ming will be described with its preferred examples. These examples are to help understand the present invention, but not to interpret its limitations Scope. The present invention provides granules (“”) that can effectively produce pharmaceutical compositions (such as unit dosage forms). The preferred form of granule application is pills. Seven people were surprised that THL-containing granules (also known as composite units) were used in tablets. Pressure

533082 A7 B7 V. Description of the invention 2 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs When shrinking or encapsulating, the phenomenon of adhesion and immersion can be reduced. In one aspect, the present invention relates to a unit dosage form comprising a plurality of pills having a diameter ranging from 025 mm to 2 mm, wherein each-granule contains tetrahydrolipstatin, a stabilizer and at least-pharmacologically Acceptable excipients. When the granules are in the form of pills; use microcrystalline cellulose. The term " stabilizer " refers to an agent with a moisture absorption rate greater than THL. The role of this stabilizer is to prevent the hydrolysis of THL. The preferred stabilizers have a moisture content of greater than 5% at 50% relative humidity. A skilled technician who has studied its performance characteristics can choose a stabilizer containing the above characteristics. Examples of such stabilizers include (but not from m-propylpropylmethylcellulose, propylpropylcellulose, polyvinylpyrrolidone, and lactose. Preferably, the average diameter of the core particles ranges from 0.05 to 5 mm. The diameter mentioned in all characteristics refers to the average diameter. Although it is best that all particles are between the listed categories, 'small or small particles that appear very little or trace are acceptable. The present invention is more A further object is a product as described above, which includes a special mixture containing THL and stabilizers, and excipients, particularly products containing polyvinylpyrrolidone and / or lactose as stabilizers. A polyvinylpyrrolidone containing (a) lactose and at least 3 weight percent of the product or (b) at least 5 weight percent of polyvinylpyrrolidone of the product. A preferred composition essentially contains about 20 to 75 weight percent Τ η L, and stabilizers of about 3 to 60 weight percent. The preferred pellets also contain micro-cellulose of about 10 to 60 weight percent. More preferred pills contain about 25 to about 7 5 weight (please Read the note on the back first Please fill in this page again if necessary).--口 -5- This paper size applies to Chinese National Standard (CNS) Α4 size (2ΐ〇χ297 quilt) ^ 33082 Staff Consumer Cooperatives Seal of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 5 3. Description of the invention (3) The percentage of THL: from about 20 to about 60 weight percent of microcrystalline cellulose; from about 1 to about 10 weight percent; sodium powder glycolate: from about 1 to about 8 weight percent Dodecyl sodium sulfate: from about 1 to about 10 weight percent of polyvinylpyrrolidone: and from about 0 to about 1 weight percent of talc. Most {Kui's pills contain about 50 weight percent of τ η L; about 3 9% by weight of microcrystalline cellulose: about 3% by weight of sodium starch glycolate: about 3% by weight of eleven sodium sulphate; about 5% by weight of polyethylene glycol ratio n each alkanone: and about 〇1% by weight of talc. This product is chemically stable and can be filled in a fast-operating encapsulation machine without sticking and soaking. In addition to the preferred stabilizers (polyvinylpyrrolidone and / or lactose), this product Invented products (ie granules) also contain other additives Agents, such as diluents, such as sucrose, or preferably microcrystalline cellulose (particularly suitable for the pills of the present invention); binders, such as pastes: surfactants, such as sodium lauryl sulfate or dioctyl sulfobutane Sodium dihydrate: and / or disintegrants, such as sodium starch glycolate. Pellets can also include corn starch as a diluent and disintegrant, and triglycerides. Pellets are preferably prepared after being squeezed out from wet mass The pellets are spherical. It can also be prepared by granulation in the rotating chassis in a fluidized bed equipment, or by coagulation and granulation in a slanted disk-like equipment or in a shear mixer. The step of preparing the pills itself is already See, for example, J. W. Conine and HR Hadley, D & CI, April 1970 ', pp. 38-41: Small solid pharmaceutical balls Spheres): A. D. Reynold, Manufacturing Chemist & Aerosol. -6-This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) ( (Please read the notes on the back before filling out this page). ^^ 衣-

1T 533082 A7 B7 4 V. Description of the invention (

News), June 1970, pp. 40-43: A new technique for the production of spherical particles: CW Woodruff and NO Nuessle 'Medicine Science Journal (J. Pharm. Sci.) No. 61 (Vol. 5) 'Pages 7 8 7-79 (1 1972); variable manufacturing of pellets obtained by the extrusion-pellet method Effect of Processing VariaMes 〇n Particles obtained by Extrusion-Spheronization Processing-and HJ Malinowski and W · Smith, Journal of Medical Science 64 (Vol. 10) ) Page 1688 _ 1692 (1975): Use of Factorial Design to Evaluate Granulations

Prepared by Spheronization) o Basically, the steps of pelleting by extrusion and ball method include the following operating units:-Wetting and kneading the active substance THL and other excipients with a suitable binder, mainly a liquid solution Powder agglomerates to obtain wet, pasty agglomerates. It is also possible to mix the adhesive with ^ powder $ before wetting and kneading: ^-Extrude this moist mass through the holes of the orifice plate with appropriate equipment (extruder) to obtain the shape of spaghetti Moist strips. The diameter of the hole can be greatly changed according to the difference of the individual products to be obtained, such as from 〇4 to 丨 0 mm ^ P-, to divide the bar into small sections, and at the same time use the main structure of the vertical cylinder ball machine to rotate Plate to form almost spherical particles. -Dry the wet pellets with appropriate drying equipment. Ruxin or shelf dryer. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling out this page) Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Seal 533082 A7 ------- B7 V. Description of the invention (5) ~-If necessary, the dried pellets can be divided into small pieces of appropriate size, or the main products can be eliminated by appropriate screening or filtering steps. Or too large. It is preferably maintained below 35 throughout the process. 〇 的 温度。 0 temperature. A further aspect of the present invention is an oral pharmaceutical preparation or composition comprising the particles. It can be simply packed in a PVC container and taken directly with a dose spoon. Other oral dosage forms are sachets, which are filled with the granules alone or added with excipients such as skim milk powder, microcrystalline cellulose, sodium hydroxycellulose sodium, and talc to form a reprocessed powder. Another possibility is to embed two capsules into a matrix transformation agent (such as microcrystalline cellulose), and then compress it into a tablet, especially a commercial bond. Rong particles can also be filled in capsules, such as hard capsules. The following examples can describe (but not limit) the present invention. Example 1 Preparation of Pills The following steps apply to a quantity of 40 kg pills at a time. a) I20 grams of sodium lauryl sulfate and 200 grams of polyacetopyrrolidone [Pov done] are stirred to dissolve in an appropriate amount of soft water. The solution was cooled at ° C (solution a). 〇〇〇〇〇th of THL, 15 600 grams of microcrystalline cellulose and 120 grams of sodium diglycolate in the South speed mixer [Diosna (DIOSNA) brand, ρ50] and mixed Mixer and shredder at low speed ",, pre-mixed for one minute (premix B). C) Add liquid A to premix β in mixer and shredder at speed I for 2.5 minutes, then Set the shredder to speed, 'η'. After 3 minutes, reduce the speed of the shredder to "Γ" for i minutes, and then discharge the substance = from the discharge valve: its temperature is between 20 and 25 ° C. (Please read the notes on the back before filling out this page)

1T 533082 5 I____ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Invention Description (6) d) The material is filled into the extruder (NIC a laboratory, E-140 type). The extruder is equipped with a screen with a standard screen size of 0.8 mm and a thickness of 1.0 mm; the screen is surrounded by a cooling device. The substance is pressed out to make a spaghetti of appropriate length. The temperature of the extrudate and the screen of the extruder is lower than 35 (extrudate d). e) Divide the extrudate D into a small amount, about 800 grams, send it to a ball machine (NICA Labs, Model S-320), and pellet the ball at 700 rpm for 3 / 4-2 minutes (wet Pill E). f) Send the cylindrical wet pellet E to a fluidized bed dryer [AEROMATIC, Model MP-1], which is equipped with a dry air supply and the input air temperature is below 35 ° C Dried into pellets with low final wet content (F) .g) The dried pellets were screened with a square sieve fitted with 0.5 mm rice and 1.25 mm sieve openings: discard smaller and larger fragments; collect. 5-1 2 5 mm portions are placed in fully sealed containers as THL pills. See pill A of Table 1 below. Example 2 Preparation of Pills The following steps apply to an amount of 6.0 kg of pills at a time. a) Using a stirrer, dissolve 180 grams of sodium dodecyl sulfate and 300 grams of polypyrrolidone in an appropriate amount of soft water. Place the beaker in a mixture of ice and water to cool the solution to about 10-15. (3 (A). B) Charge 1800 g of TH L, 3 120 g of microcrystalline cellulose, and 600 g of sodium starch glycolate into a high-speed mixer (Diosna brand, model P 5 0) and use The mixer and shredder are pre-mixed at low speed "I" for 1 minute (B). -9-This paper size applies Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page) Order ^ 3082

2. Description of the invention (Add Luoxin A to premix B and mix in mixer and shredder at speed I for 2.5 minutes, then set the shredder at speed "η". After 3 minutes, add shredder The speed is reduced to "", hold for ❸ minutes, and then the material is sludged out through the discharge valve: its temperature is between 20 and 25. The material is filled into the extruder and processed according to the example. E) Divide the extrudate into small quantities, about 800 grams, and send them to a fluidized bed dryer equipped with a rotary granulator and a dry air supply (Aromedic, MP-〗 type), The ball was pelletized at 500 rpm for 3 minutes (E). 0 The cylindrical wet pellet E was dried in the same equipment under the condition that the input air temperature was lower than 3 5 π, and became a pellet with a low final moisture content (F). 2 ~, g) The dried pills are screened with a sieve with a size of 0.5 mm and i 2 5 mm: discard the smaller and larger fragments: collect 0.5_ 1 h for In a completely closed container. Mao Yi B. " The composition of the pills A and B of Table 1 is shown in Table i: The main 1 pill with empty 1 is shown in weight percentage. (Shown) Agents:

Printed finely ground THL excipient microcrystalline cellulose by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Paper

NS secret

39 3 52 00.

---- (Please read the notes on the back before filling this page)

533082 A7 B7 V. Description of the invention (8) Example 3 Preparation of Pills Pills containing the following compositions were prepared in a similar manner to Pills A and B: Table 2 Pill Formula (shown in weight percent) F1 F2 F3 F4 F5 F6 THL 29.1 30.2 50 50 50 50 Lactose 〇 γ JJ.J 34.0 7 21 12 Microcrystalline cellulose 23.6 20.8 36 19.5 21 41 Sodium starch glycolate 9.1 9.4 3 3 9.5 3 Sodium dodecyl sulfate 1.1 1.1 1 1 3 1 ( Yu Baiwei; East) Polyethylene bispyrrolidone 3.6 4.5 3 3 4.5 5 Medium chain triglyceride 2.5 (Please read the precautions on the back before filling this page) Clothing. Order Staff Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed, Example 4 Preparation of the final dosage form Mix any one of pellets A or B (Examples 1 and 2 above) with talc, and package with pellet filling equipment (formulations C, E): Or pill A or The mixture of B, skimmed milk powder, microcrystalline cellulose, and talc are filled into a sachet (formulation D). A similar mixture was compressed into a chewable lozenge (Formulation F). The compositions of the final dosage forms C, D, E, F are shown in Table 3. -11-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 533082 A7

7 B V. Description of the invention (9) Table 3: Final dosage form composition (shown in mg / dose) Formula CDEF Final effect agent 120.0 60.0 30.0 30.0 mg Pill type effect agent: Pill A 240.0 120.0 Noodles _ Sun mg pill B Yizheng 100.0 100.0 mg Excipients: skimmed milk powder (granular) 3875.0 mg microcrystalline cellulose + sulfomethyl-cellulose sodium [AVIC (AVICEL RC-type) 1000.0 mg microcrystalline cellulose 1888.0 mg talc 0.24 5.0 0.1 2.0 mg Magnesium Stearate 10.0 mg Total Filling Weight of Hard Capsules 240.24 100.1 mg Total Filling Weight of Sachets 5000.0 mg Chewable Tablets Weight 2000.0 mg (Please read the notes on the back before filling out this page) Central Bureau of Standards, Ministry of Economic Affairs The detailed composition formula C of capsules filled with pills A printed by employee consumer cooperatives is shown in Table 4: -12- This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) 533082 A7 B7 V. Description of the invention (1.) Table 4: Manufacturing weight per batch = 160.160 kg = 666,666 capsules filled weight = 240.24 mg into Content mg / capsule 666,666 Capsule content (kg) THL 120.00 80.000 Microcrystalline Cellulose (Aiweixie PZ-101) 93.60 62.400 Sodium starch glycolate [PRIMOJEL] 7.20 4.800 Sodium lauryl sulfate 7.20 4.800 Polyvinylpyrrolidone (VERSI) (Κ-30) 12.00 8.000 Talc 0.24 0.160 Total 240.24 mg 160.160 kg (Please read the precautions on the back before filling out this page) Clothing, 1T Example 5 Preparation and preparation of THL-containing particles Ingredients mg / capsule 1. THL 120 2. Microcrystalline cellulose 93.6 3. Sodium starch glycolate 7.2 4. Polyacetonylpyrrolidone 12.0 5. Dodecyl sodium sulfate 7.2 Total 240.0 Ministry of Economy Central Standard Printed by the Bureau's Consumer Cooperatives 1. Dissolve polyvinylpyrrolidone and sodium lauryl sulfate in water. 2. Mix THL, microcrystalline cellulose and sodium starch glycolate for 10 minutes and -13- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 533082 5. Description of the invention (11

Step 1 / Granulation granulation · J * At 30 C or less than 3 〇4. The granules are filled with hard granules and displayed through a sieve 6

2 Dissolve polyvinylpyrrolidone and sodium lauryl sulfate in water (please read the precautions on the back before filling in this page).-Order_ After printing the THL, anhydrous lactose and Dianfen sodium glycolate was mixed for ⑺ minutes and the solution of step 1 was granulated: at 30 ° C or below 30X: the granules were dried and passed through a No. 20 sieve. The granules were packed in No. 1 hard gelatin capsule. The invention has been described using its preferred examples. When skilled technicians read these instructions, they will think of alternatives. These changes included in the scope and spirit of the present invention are limited only by the scope of the following patent applications and their equivalents. @ 4 14- This paper size applies to China National Standard (CNS) A4 (2l0x297mm)

Claims (1)

Patent No. 2 _5_Please file for another profitable replacement (January 1992) The scope of the patent application is “L”, which contains 25 ^^ · 25 mm to 2 mm eve number of particles, each particle contains tetrahydrolipstatin (, etrahydrollpstatln), a stabilizer and at least one pharmaceutically acceptable The accepted martial arts dS particles are provided in the form of pellets, each pellet containing microcrystalline cellulose. 2. · According to the pharmaceutical composition according to item 1 of the patent claim, the granules are pellets or granules, especially the average diameter of the pills or granules is from 0.5 mm to 1.5 mm. 3. The pharmaceutical composition according to item 2 of the scope of the patent application, wherein the stabilizer is selected from the group consisting of polyethylene glycol, lactose, and polyethylene glycol, and: mixture, hydroxypropylmethyl Group of cellulose and hydroxypropyl cellulose. 4_: The pharmaceutical composition according to item 3 of the scope of patent application ', which contains at least 5 percent by weight of polyvinylpyrazole. A mixture of fudge and pyrrolidone, wherein the composition contains up to 3% by weight of polyethylene terephthalone. 6. The pharmaceutical composition according to claim 2 of the scope of patent application, wherein the pharmaceutical formulation "the excipient is a surfactant, diluent, or disintegrant. Essentials 7. The pharmaceutical composition according to item 6 of the scope of the patent application, wherein the excipient is a surfactant, especially the surface activity thereof: :: monobasic sodium sulfate or dioctylsulfosuccinic acid sodium. … 8. The pharmaceutical composition according to item 6 of the scope of the patent application, wherein the excipient for receiving the medicine is a diluent, and especially the diluent is diluted to the upper level. M is microcrystalline fiber 9. 10. 11. 12. 13. 14. The scope of patent application is vegetarian, sucrose or corn starch. According to the medicine disintegrating agent in the scope of application patent No. 6, especially the disintegration therein, 'the excipients are dipyrrolidone, cross-linked Carlyon E 0 ^ Lussner (CrOss-cai * m〇l Ose sodium) or low-substituted hydroxypropyl cellulose. The pharmaceutical composition according to item 2 of the scope of patent application, which contains 20 to 75 weight percent: tetrahydroribostatin; 3 to 60 weight percent diazepam, and 10 to 60 weight percent Percent microcrystalline cellulose. The pharmaceutical composition according to the scope of application for patent No. 丨 0, which contains 25 to 75% by weight of tetrahydroribostatin; from 20 to 60% by weight of microcrystalline cellulose; from 1 to 丨〇% by weight of sodium starch glycolate; from i to 8% by weight of sodium lauryl sulfate; from 1 to 10% by weight of polyvinylpyrrolidone; and from 0 to 1% by weight of talc. The pharmaceutical composition according to item 11 of the scope of patent application, which contains 50% by weight of tetrahydrolipstatin; 39% by weight of microcrystalline cellulose; 3% by weight of Dianfen glycol acid steel; 3 weight percent of twelve calcined sodium valerate; 5 weight percent of polyvinylpyrrolidone; and 0.1 weight percent of talc. The pharmaceutical composition according to claims 1, 2 and 10 to 12 of the scope of the patent application is a unit dose. A pharmaceutical composition according to item 1 of the scope of patent application, comprising 120 mg of tetrahydrolipstatin; 9 3.6 mg of microcrystalline cellulose; 7.2 mg of sodium starch glycolate; 7.2 mg of twelve roasts Sodium sulphate; 12 mg of Polyethylene I: Luo Yuan Ketone; and 0.24 mg of talc. -2- 533082 8 8 8 8 A B c D 6. Scope of patent application 15. The pharmaceutical composition according to item 14 of the scope of patent application is a unit dosage form. -3- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)