JPH01156913A - Medicine composition containing a large quantity of medical substances and method for its preparation - Google Patents

Abstract

PURPOSE: To obtain the subject medicinal composition in a bead form which contains an maximized amount of the medicine and can be readily prepared by extrusion and/or sphering by using an excipient containing, as bases, non- lipophilic binding and plasticizing agent such as fine crystalline cellulose and starch and, when necessary, a water-soluble binder. CONSTITUTION: This high drug-content medicinal composition contains 80wt.%, particularly 80-95wt.% of a drug (particularly erythromycin, captopril or zofenopril), 1-15wt.%, particularly 2-12wt.% of a an excipient containing, as a base, a non-lipophilic binding and plasticizing agent (particularly fine crystalline cellulose is suitable) and a starch (sodium starch-glycolate or gelled starch is suitable) and, when necessary, a water-soluble binder. These components are combined with a granulation liquid to prepare a moistened formulated material, which is extruded into beads and dried thereby producing the objective medicine composition.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a pharmaceutical composition with a high drug content and a method for producing the same, and more particularly, to a pharmaceutical composition containing a drug in the form of beads (
The present invention relates to pharmaceutical compositions (or spherical or spherical) and a method for producing them by an improved extrusion/spheronization method.

Prior art and problems to be solved by the invention Bead-shaped or spherical (diameter 0.5-1.5 rItfI
The extrusion/spheronization method used for manufacturing the pharmaceutical formulation of L) is:
It is a relatively complex technology. Such manufacturing methods require tri-blending of drug and excipients, wet granulation (aqueous or non-aqueous) of the compounded materials, extrusion through a window-sized screen, and spheronization. During the extrusion process, the formed wet compound mass is compressed into a cylindrical strand. To form a sphere, the cylindrical strand is placed in a spheronizer. The device is a simple unit with a rotating plate. The cylindrical strands are crushed under the action of a rotating plate, and the similar strands are tumbled/roved.
(ping) action to obtain a sphere.

To carry out this step, the drug and excipient blend must exhibit a high degree of plasticity to allow the extrusion/spheronization (deformation) process.

Microcrystalline cellulose (Avicel, various Avicel grades: PHI O1, PH102, PH103,
PH105, RC591, RC581CL-611). Additionally, the liquid used in wet mass formulation increases the plasticity of the blend. That is, increasing the wettability of the material increases the plasticity of the blend. However, spheronizing an overly wet extrudate can lead to agglomeration (ball-up), so the amount of liquid must be carefully controlled.

In order to impart an acceptable degree of plasticity to the drug and excipient blend to enable the extrusion/spheronization process to be carried out, the blend should contain at least 75-80% (by weight) drug. It was found that it should not contain any component and should not contain less than 15-20% microcrystalline cellulose component.

Although the conventional extrusion/spheronization methods described above are satisfactory for producing beads containing less than 75-80% drug,
Beads containing as much as 80% drug may be required. For example, erythromycin beads containing 70-75% erythromycin and 15-20% microcrystalline cellulose do not have the desired drug dissolution rate due to the presence of large amounts of microcrystalline cellulose;
It was found that this drug dose did not fit well into size O capsules.

Structure and Effects of the Invention That is, the present invention provides a novel bead that can contain 80% or more of a drug component, has a desired drug dissolution rate, and can be manufactured in an IEly manner using an extrusion/spheronization method. The present invention provides a pharmaceutical composition in the form of a pharmaceutical composition. This is truly surprising and unexpected. This is because, until now, it was thought that beads containing more than 80% drug could not be easily produced due to plasticity problems during extrusion and/or agglomeration problems during spheronization. be.

The pharmaceutical composition according to the present invention has a bead shape, and the beads contain 980% or more of the drug, and 15% or less (preferably 10% or less) of a non-lipophilic binder and plasticizer that imparts the desired drug dissolution rate. agents (e.g. microcrystalline cellulose), starch-based excipients (e.g. sodium starch glycolate or gelling starch) that bind and plasticize the blend and control water or liquid distribution to inhibit agglomeration during the process. ), and optionally a water-soluble binder to reduce the friability of the final beads. As will be apparent from the description below, granulating agents such as ethanol/water mixtures are added during the process to improve blend properties.

Furthermore, the present invention provides a method for manufacturing the above-mentioned bead-shaped pharmaceutical composition, which comprises adding up to 15% of the drug in the final product to a binder-plasticizer, a starch-based excipient, and optionally a water-soluble aqueous and/or non-aqueous, e.g. water/ethanol) to form a wet blended mass, extrude the wet blended mass to form an extrudate, and then extrudate the extrudate. It consists of a step of spheroidizing to form beads. The resulting beads may be dried and further coated if necessary.

The surprising points in the present invention are as follows. That is, the binder and plasticizer (for example, microcrystalline cellulose)
When present in amounts of less than 5%, preferably less than 10%, the plasticity of the wet compound mass is reduced, but the desired rate of bead dissolution is achieved. The presence of starch excipients (eg, sodium starch glycolate) enhances blend properties, including plasticity, allowing for effective extrusion and spheronization without agglomeration. By the presence of a water-soluble binder (hydrolyzed gelatin), the amount of granulation liquid can be controlled so that agglomeration during spheronization is avoided. Greater control of the spheronization process is achieved by the presence of an aqueous/non-aqueous granulating agent. That is, the blend has properties characterized by both extrusion and controlled spheronization. This property is sufficiently provided even when the drug is present in a high content of 80% or more and a very small amount of binder/plasticizer (eg, microcrystalline cellulose) is used.

The beads of the present invention contain 80 to 96% (preferably 80 to 9%)
4%) of the drug. Drugs that may be used include angiotensin converting enzyme (ACEIJ) inhibition, eg U of Ondetsutei et al.

Δ Substituted pro-IJ derivatives described in S6 Patent No. 4105776 (preferred is captopril, i.e. 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline), U of Ondetsutei et al.

S, the ether or thioether mercaptoacylprolines described in Patent No. 4316906 (zofenopril is preferred), the above U, S, Patent No. 4374829
Carboxyalkyl dipeptide derivatives (enalapril, i.e. N-(1-ethoxycarbonyl-3
-phenylpropyl)-L-alanyl-L-proline is preferred).

Other suitable ACE inhibitors include:

The above U, S, the phosphinylalkanoylprolines described in Patent No. 4168267, the above U, S, Patent No. 43
Phosphinylalkanoyl-substituted prolines, U, S, including fosinopril as described in No. 37201.

1-(3-mercapto-2-methylpropanoyl)prolyl amino acid derivatives described in Patent No. 4248883,
U,S, phosphonamidates described in Patent No. 4432971, and phosphonates described in U,S, Patent No. 4452790, such as (S)-1-[:6-amino-2-[[hydroxy(4 -phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolinker.

The beads of the invention may contain other drugs that are absorbed in the upper intestine, such as antihypertensives such as nifedipine or verapamil, diuretics such as hydrochlorothiazide, pendroflumethiazide or chlorthalidone, propranolol HCI! or β-blockers such as atenolol, and anti-infectives such as erythromycin, β-lactams, penicillin, macrolide or lincosamide antibiotics.

The non-linoleum binder and plasticizer is 1 to 12% or more (but not more than 15%), preferably 2 to 8% in the beads.
exists in an amount of A preferred binder and plasticizer for use in the beads of the present invention is microcrystalline cellulose. The binder in this case plays the role of an excipient. However, other binders may also be used on their own or in combination with known excipients.

Such binders may be hydrophilic polymers or hydrocolloids formed from water-swellable polymeric materials such as cellulosic polymers or rubber shavings.

Starch-based excipients improve all blending properties, including the extruded wet compound mass, the quality properties of the resulting extrudate, and enable controlled spheronization. In theory, starch-based excipients affect the availability of water in the blend. During extrusion, sufficient water (or other liquid) is utilized to plasticize and lubricate the blend. However, during spheronization, starch-based excipients prevent or retard the accumulation of water/liquid on the beach surface, thereby inhibiting aggregate 4.

The amount of starch-based excipients is 0.5-12% in the beads
, preferably 1 to 10%. A preferred starch-based excipient for use in the beads of the invention is sodium starch glycolate. Other suitable starch-based excipients include, but are not limited to, corn starch, gelling starch (Starch 1500), croscarmellose or cross-linked polyvinylpyrrolidone.

Water-soluble binders are optionally used to reduce the liquid volume of the extruded compound, improve plasticity, and prevent spheronization from occurring during spheronization. This contributes to the production of beads that are less brittle than previous beads. Therefore, in preferred embodiments, the amount of water-soluble binder is between 0.2 and 5%, preferably between 0.5 and 3% in the beads. Examples of suitably used water-soluble binders include, but are not limited to, hydrolyzed gelatin, polyvinylpyrrolidone or low viscosity hydroxypropyl methylcellulose, with hydrolyzed gelatin being preferred.

The optional water-soluble binder is dissolved in the granulation liquid, which liquid is preferably water or an ethanol/water solution containing 0-75% (preferably 0-30%) ethanol. . Other granulation liquids may also be used, including isopropyl alcohol, methanol or other suitable organic solvents.

Preferred beads according to the invention contain 80-95% drug, 2-5% microcrystalline cellulose, 2-5% starch-based excipient (e.g. sodium starch glycolate or gelled starch) and optionally Te 0.5-3
．． 5% water-soluble binder (hydrolyzed gelatin is preferred)
It consists of a core part containing (in addition, % is a ratio to a core part).

In addition, inert fillers may be used if necessary, such as lactose, sucrose, mannitol, xylitol, and the like.

When forming beads according to the production method of the present invention, first,
For example, using conventional blending equipment, the drug and starch-based excipient may be combined with a granulating agent [e.g., water or ethanol/water (3:1 (below)] to form a wet blended material. Then, for example, Nika (N
1ca) Using an extruder, Luwa extruder or other type of extruder, extrude the wet blended mass to form an extrudate, which is then transferred to a spheronizer (e.g. Nika, Luwa or other type) to make beads of appropriate particle size.

The beads can then be dried in a tray oven dryer or a fluidized bed dryer. If necessary, such beads may be pan coated, for example, with a solution or dispersion of film formers and plasticizers.
Coating may be performed using g) or fluidized bed coating.

The beads thus obtained can be filled into hard shell capsules to form a preparation, which is administered once to four times a day.
Approximately 5 to 300 cm per serving, preferably approximately 6.25 to 25
Administered in single or divided doses of 0.

The following examples are preferred embodiments of the invention.

Example 1 A bead capsule formulation containing 92.5% erythromycin and having the following composition is manufactured according to the following procedure.

Composition components Weight % Erythromycin... 92.5 Sodium starch glycolate (Primojel)...
3 Microcrystalline cellulose (Avicel PH101 binder and plasticizer)... 3.
5. Hydrolyzed gelatin (binder added to the granulation liquid as a 5% w/v solution)... 1. Knead the above ingredients in a planetary mixer using water and 725% ethanol as the granulation liquid, and moisten. Form a blended material. This wet compounded mass is passed through a N1caE140 extruder to form an extrudate (1M diameter or less). The extrudate was then exposed to N
Form beads by passing through an lca spheronizer. The beads are then placed in a side oven dryer or fluidized bed dryer at 50°C.
Dry with. A portion of the beads thus obtained is filled into a hard shell capsule to form a bead capsule formulation of the present invention.

Example 2 According to the procedure described in Example 1, a capsule formulation of erythromycin beads having the following composition was manufactured.

Composition components Weight % erythrophycine (Ba5e, USP)... 87.5 Sodium starch glycolate... 2 Gelled starch... 7 Microcrystalline cellulose... 3.5 Water is used as the granulation liquid Patent applicant: E.R. Squibb & Sump, Inc. Agent: Patent attorney Yoshihiro Seishi and one other person

Claims (1)

[Claims] 1. 80% by weight or more of the drug in the total composition, 1-15% by weight of a non-lipophilic binder and plasticizer, and 0.5-12% by weight of a starch-based excipient. and, if necessary, a water-soluble binder. 2. The composition according to claim 1, wherein the drug content is 80 to 95% by weight. 3. Content of non-lipophilic binder and plasticizer is 2-12% by weight
The composition according to claim 1, wherein the content of starch-based excipient is 1 to 10% by weight. 4. Contains a water-soluble binder, the amount of which is 0.2 to 5% by weight
The composition according to claim 1. 5. The composition of claim 1, wherein the starch-based excipient is sodium starch glycolate, cornstarch, croscarmellose, gelled starch or crosslinked polyvinylpyrrolidone, or a mixture thereof. 6. The composition according to claim 1, wherein the drug is erythromycin or an angiotensin converting enzyme (ACE) inhibitor. 7. Claim in which the ACE inhibitor is selected from the group of substituted proline derivatives, ether or thioether mercaptoacyl prolines, carboxyalkyl dipeptide derivatives, phosphinylalkanoylproline derivatives, phosphonamidate derivatives, phosphonate derivatives and prolyl amino acid derivatives. Composition according to item 6. 8. ACE inhibitors include captopril, zofenopril,
7. The composition of claim 6, which is fosinopril or enalapril. 9. Claim 1, wherein the drug is captopril or erythromycin, the binder and plasticizer is microcrystalline cellulose, the starch base excipient is sodium starch glycolate or gelled starch, and the water-soluble binder is hydrolyzed gelatin. Composition of. 10. A method for producing a beaded pharmaceutical composition containing 80% by weight or more of a drug, the drug, a non-lipophilic binder and plasticizer, a starch-based excipient and optionally a water-soluble adding a granulating liquid to the binder to form a wet blended mass and extruding the wet blended mass to form an extrudate;
A method for producing a bead-like pharmaceutical composition with a high drug content, comprising forming the extrudate into beads, and then drying the beads. 11. The method according to claim 10, wherein the binder and plasticizer is microcrystalline cellulose, the starch base excipient is sodium starch glycolate, and the water-soluble binder is hydrolyzed gelatin.