JP2804048B2 - High drug content pharmaceutical composition and method for producing the same - Google Patents

Description

The present invention relates to a pharmaceutical composition having a high drug content and a method for producing the same, and more particularly, to a bead-shaped (or spherical) pharmaceutical composition containing 80% by weight or more of a drug, It relates to an improved extrusion / spheronization process.

BACKGROUND OF THE INVENTION Problems to be solved by the prior art and the invention The extrusion / spheronization process used for the production of beaded or spherical (0.5-1.5 mm diameter) pharmaceutical preparations is a relatively complex technique. Such manufacturing methods require dry blending of the drug and excipient, wet granulation (aqueous or non-aqueous) of the compounded material, extrusion from a screen of fixed pore size and spheronization. During the extrusion process, the formed wet compound material is compressed into cylindrical strands. The cylindrical strand is placed in a sphering device to form a sphere. The device is a simple unit with a rotating plate. The cylindrical strand is crushed under the action of a rotating plate,
The short strand is deformed by tumbling / roping action to obtain a sphere.

In order to perform this step, the drug and excipient blend must exhibit a high degree of plasticity and allow for an extrusion / spheronization (deformation) step. To provide the required plasticity, the microcrystalline cellulose (Avicel, various Avicel grades: PH101, PH102, P
H103, PH105, RC591, RC581CL-611). Further, the liquid used in the wet mass formulation increases the plasticity of the blend. That is, if the wettability of the material increases, the plasticity of the blend increases. However, spheroidization of an excessively wet extrudate causes agglomeration (ball up), so that the amount of liquid must be carefully controlled.

To impart an acceptable degree of plasticity to the drug / excipient blend so that the extrusion / spheronization step can be performed, the blend should contain at least 75-80% (wt%, and so forth) of the drug. It was previously known that no component should be contained and no more than 15-20% of the microcrystalline cellulose component.

The conventional extrusion / spheronization method described above is satisfactory for producing beads containing the drug in an amount of 75-80% or less.
% Of the drug may be required. For example, 70-75% erythromycin and 15-
Erythromycin beads containing 20% microcrystalline cellulose do not have the desired drug dissolution rate due to the presence of large amounts of microcrystalline cellulose, and in addition, are well suited for size 0 capsules at this drug dose. I couldn't understand.

In other words, the present invention provides novel beads that can contain at least 80% of a drug component, have a desired drug dissolution rate, and can be easily manufactured using an extrusion / spheronization method. The present invention provides a pharmaceutical composition in a solid form. This is truly surprising and unexpected. Because, until now,
Beads containing more than 80% of the drug may have problems due to plasticity problems during extrusion and / or cohesion problems during spheronization.
This is because it was thought that it could not be easily manufactured.

The pharmaceutical composition according to the invention has the form of beads and more than 80% of erythromycin in the beads, less than 15% (preferably less than 10%) of a non-lipophilic binder which gives the desired drug dissolution rate. A plasticizer (ie, microcrystalline cellulose), a starch-based excipient (eg, sodium starch glycolate or gelling) that binds and plasticizes the blend and controls the distribution of water or liquids to prevent agglomeration during the process. Starch), and optionally a water-soluble binder to reduce the friability of the final beads. As will be apparent from the description below, a granulating agent such as an ethanol / water mixture is added during the process to improve the blending characteristics.

Further, the present invention provides a method for producing the above-mentioned beaded pharmaceutical composition, wherein the method comprises erythromycin in the final product.
15% or less of microcrystalline cellulose, starch-based excipients and, optionally, water-soluble binders and granulating agents (aqueous and / or non-aqueous, for example, water / ethanol) to form a wet compound material. Extruding the wet blended material to form an extrudate, and then spheroidizing the extrudate to form beads. The resulting beads may be dried and, if necessary, coated.

Surprising points in the present invention are as follows. That is, if microcrystalline cellulose is present in an amount of 15% or less, preferably 10% or less, the plasticity of the wet compounded material is reduced, but a desired bead dissolution rate can be obtained. The presence of starch-based excipients (eg, sodium starch glycolate) enhances blending properties, including plasticity,
Effective extrusion and spheroidization can be performed without agglomeration. The presence of a water-soluble binder (hydrolysed gelatin) can control the amount of granulated liquid so that agglomeration during sphering can be avoided. Further control of the sphering step is achieved by the presence of the aqueous / non-aqueous granulating agent. That is, the blend has properties that allow for both extrusion and controlled spheroidization. This property is sufficient even when erythromycin is present at a high content of 80% or more and a very small amount of microcrystalline cellulose is used.

The beads of the present invention are 80-96% (preferably 80-94%)
Of erythromycin.

Microcrystalline cellulose is present in the beads in an amount of 1 to 12% or more (but not more than 15%), preferably 2 to 8%. Microcrystalline cellulose plays an excipient role.

Starch-based excipients improve all blending properties, including the quality properties of the extruded wet compound and the resulting extrudate, and allow for controlled spheronization. In theory, starch-based excipients affect the effectiveness of moisture in the blend. During extrusion, sufficient water (or other liquid) is utilized to plasticize and lubricate the blend. However, during sphering, the starch-based excipients prevent or delay the accumulation of water / liquid on the bead surface, thereby suppressing aggregation.

The amount of starch base excipient is 0.5-12% in the beads,
Preferably it is 1 to 10%. A preferred starch-based excipient for use in the beads of the present invention is sodium starch glycolate. Other suitable starch-based excipients include, but are not limited to, corn starch, gelled starch (starch 1500), croscarmellose.

Water-soluble binders are used as needed to reduce the amount of liquid in the extruded compound, improve plasticity, prevent agglomeration during spheroidization, and It contributes to the production of beads having less brittleness than the beads. Thus, in a preferred embodiment, the amount of water-soluble binder is 0.2-5%, preferably 0.5-3%, in the beads. Specific examples of the water-soluble binder suitably used include, but are not limited to, hydrolyzed gelatin, polyvinylpyrrolidone or low-viscosity hydroxypropylmethylcellulose, with hydrolyzed gelatin being preferred.

The optional water-soluble binder dissolves in the granulated liquid,
Preferably such a liquid is water or an ethanol / water solution containing 0-75% (preferably 0-30%) of ethanol. Other granulating liquids can also be used, for example, isopropyl alcohol, methanol or other suitable organic solvents.

Preferred beads according to the invention are 80-95% erythromycin, 2-5% microcrystalline cellulose, 2-5% starch base excipients (eg sodium starch glycolate or gelled starch) and optionally 0%. .
Consists of a core portion containing 5 to 3.5% of a water-soluble binder (preferably hydrolyzed gelatin) (where% is a ratio to the core portion).

If necessary, an inert bulking agent can be used. For example, lactose, sucrose, mannitol,
Xylitol and the like.

When forming beads according to the production method of the present invention, first, erythromycin, microcrystalline cellulose and starch base excipient are added using, for example, a conventional blending apparatus.
Optionally mix thoroughly with a granulating agent (eg, water or ethanol / water (3: 1 or less)) containing a water-soluble binder (eg, hydrolysed gelatin) to form a wet blended material. The wet compounded material is then extruded using, for example, a Nica extruder, Luwa extruder, or other type of extruder to form an extrudate, which is then spheronized (eg, Nika, Luwa or Through other types)
Use beads of an appropriate particle size. The beads can then be dried in a tray oven drier or a fluid bed drier. If desired, the beads may be coated, for example, with a pan coating or fluid bed coat, using a solution or dispersion of a film former and a plasticizer.

The beads thus obtained can be filled into hard shell capsules to form a preparation, which is administered in a single or divided dose of about 5-300 mg, preferably about 6.25-250 mg, once to four times a day. Is administered.

The following examples are preferred specific examples of the present invention.

Example 1 A bead capsule formulation containing the following composition containing 92.5% erythromycin is manufactured according to the following procedure. Composition Component Weight% erythromycin ... 92.5 sodium starch glycollate (Primojel) ... 3 binding added microcrystalline cellulose (Avicel PH 101 binder and plasticizer) ... 3.5 5% hydrolysed gelatin (granulation liquid w / v dissolved solution Agent) ... 1 The above components were converted into granulated liquid with a planetary mixer as water.
Kneading with 25% ethanol to form a wet blended material. Pass this wet compound through a Nica E140 extruder,
Form extrudates (diameter 1 mm or less). The extrudate is then N
The beads are formed by passing through an ica spheronizer. The beads are then dried at 50 ° C. in a tray oven or fluid bed dryer. A portion of the beads thus obtained is filled into a hard shell capsule to form the 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 is produced. Composition Component Weight% erythromycin (Base USP) ... 87.5 sodium starch glycollate ... 2 gelling starch ... 7 Microcrystalline cellulose ... 3.5 It should be noted that except for using water as the granulation liquid, Example 1
The core part is manufactured in the same manner as described above.

Continuation of the front page (72) Inventor Man Marie Delagi, England England, El 60.1 Waikyu, Merseyside, Willard, Heswall, Heythrop Drive No. 8 (56) References JP-A-53-115811 (JP, A) (58) Fields surveyed (Int. Cl. ⁶ , DB name) A61K 9/16 A61K 47 / 30,47 / 36,47 / 38

Claims (8)

(57) [Claims] Claims: 1. A granulated liquid is added to a drug, a non-lipophilic binder and plasticizer, a starch-based excipient and optionally a water-soluble binder to form a wet blended material. The extrudate is formed by extruding the wet compounded material, the extrudate is formed into beads, and then the beads are dried. A high drug content beaded pharmaceutical composition comprising 1 to 15% by weight of microcrystalline cellulose and 0.5 to 12% by weight of a starch base excipient as an oily binder and a plasticizer. 2. An erythromycin content of 80 to 95% by weight.
The composition according to claim 1, which is: 3. The content of microcrystalline cellulose is 2 to 12% by weight.
The composition according to claim 1, wherein the content of the starch base excipient is 1 to 10% by weight. 4. It contains a water-soluble binder, and its amount is 0.2-5.
2. The composition of claim 1, wherein the composition is in weight percent. 5. The composition according to claim 1, wherein the starch base excipient is sodium starch glycolate, corn starch, croscarmellose or gelled starch, or a mixture thereof. 6. The composition according to claim 1, wherein the starch base excipient is sodium starch glycolate or gelled starch, and the water-soluble binder is hydrolyzed gelatin. 7. A process for producing a high drug content beaded pharmaceutical composition according to claim 1, comprising a drug, a non-lipophilic binder and plasticizer, a starch base excipient and optionally a starch base excipient. Adding a granulating liquid to a water soluble binder to form a wet blended material, extruding the wet blended material to form an extrudate, forming the extrudate into beads, and then drying the beads. A method for producing a beaded pharmaceutical composition having a high drug content. 8. The method according to claim 7, wherein the starch base excipient is sodium starch glycolate, and the water-soluble binder is hydrolyzed gelatin.