TW201347763A - Pharmaceutical composition including low-dose of active ingredient and preparation method thereof - Google Patents

Abstract

A pharmaceutical composition includes low-dose of active ingredient, an anti-sticking agent and pharmaceutically acceptable excipient. The low-dose of active ingredient is homogenously dispersed in the anti-sticking agent and the weight ratio between anti-sticking agent and low-dose of active ingredient is 0.5-20. The anti-sticking agent includes SiO2, Talc, a cellulose disintegrant, a hydrophobic disintegrant or the combinations thereof. A preparation method for a pharmaceutical composition containing low-dose of active ingredient is also herein provided.

Description

Low-dose medicinal active ingredient pharmaceutical composition and method of producing the same

The present invention relates to a pharmaceutical composition and a method for producing the same, and more particularly to a pharmaceutical active pharmaceutical composition comprising an anti-adhesive agent and a method for producing the same.

The main component of the solid preparation generally accounts for more than 10% of the total weight, and the content uniformity portion is relatively innocent, and if it is less than 10%, the problem of content uniformity is likely to occur. When the main component is less than 5% or less, it is a low dose, and the problem of uniformity of content is liable to occur.

In addition to the problem of uniformity of content, when the low-dose pharmaceutical active ingredient collapses in the tablet, the active ingredient is easily adsorbed by the excipient due to the electrostatic force and cannot be completely released, which causes another problem.

Therefore, these two problems need to be overcome when developing low-dose drugs. Dissolving the main component or uniformly suspending it in a solvent, and then spraying it onto the carrier in the excipient, so that the main component can be smoothly released when the tablet is broken is often used to overcome the problem, such as Bristol-Myers Squibb. (Basic Squibb) The company developed the drug Beleck film ingot 0.5 mg, the main component of which is Antecavi, which accounts for about 0.25% of the total ingot weight. It belongs to the very low dose of the drug, which is the representative of the low dose. drug. However, the adsorption and electrostatic forces of its main components are still difficult points in the manufacture of this drug. Therefore, if this problem can be overcome, the use mode will solve the problem of low dose smoothly.

In the case of Antecavi, Antecavir is a clinical antiviral agent currently used to treat hepatitis B infection. In U.S. Patent No. 5,206,244, Zahler et al. disclose Antecavi and its use in the treatment of hepatitis B. Zahler discloses that an effective antiviral dose for oral or parenteral administration can range from about 1.0 to 50 mg per kilogram of body weight and reveals that the intended dose is administered several times daily at appropriate intervals.

The Republic of China Patent No. I287988 discloses a preparation of an Antequavi composition The method is to carefully deposit Antecavi on the surface of the carrier matrix particles. That is, using a solution formed by antecoxivir and a binder substance in a solvent, the solution is simultaneously sprayed or air-flowed to the running carrier matrix particles at a temperature ranging from about 25 ° C to about 80 ° C. On to complete this step. Particle agglomeration can be minimized by the above control conditions.

Inevitably, a generally low dose pharmaceutical composition will dissolve or uniformly suspend the main component in a solvent and then spray the carrier in the excipient to overcome the problem of content uniformity. However, since the main component is dissolved in the solvent or is used in the solvent for a long time, the main component is increased in reaction with the solvent, and the impurity is easily derivatized.

Since the former case is sprayed in a dissolved or suspended state, the main component is coated on the carrier, which easily causes two problems in the above stage: 1. When the contact area is large, Antecavi is likely to be adsorbed due to electrostatic force. Phenomenon; 2. Controversy over stability due to changes in the physical properties of Antkawi.

Furthermore, in the preparation of a pharmaceutical composition containing less than or equal to about 1 mg of entecavir, especially a tablet or capsule, mixing the Antecvir active substance with the excipient in a simple manner does not produce a good uniformity. Compositions, and conventional granulation methods are also not suitable for pharmaceutical compositions containing low doses of active substances.

In summary, how to prepare a pharmaceutical composition containing the low-dose active substance Antecavir, and thus effectively treating the hepatitis B virus is an urgent problem to be solved.

The present invention provides a pharmaceutical composition which can remove a drug composition containing a low dose of an active substance by an anti-adhesive agent to remove the adsorption and electrostatic force of a low-dose pharmaceutically active ingredient such as entecavir to achieve a pharmaceutical product. Effective release. The pharmaceutical composition is evaluated by Antecavi, thereby effectively treating the hepatitis B virus.

According to an embodiment, the present invention provides a pharmaceutical composition comprising: a low dose of a pharmaceutically active ingredient, an anti-adhesive agent, and a pharmaceutically acceptable excipient. The pharmaceutically active ingredient comprises from about 0.25 to 5% by weight of the pharmaceutical composition. Pharmaceutical active ingredient system It is uniformly dispersed in the anti-adhesive agent, and the weight ratio of the anti-adhesive agent to the pharmaceutically active ingredient is 0.5-20, and the anti-adhesive agent comprises ceria, talc, cellulose, hydrophobic disintegrating agent or a combination thereof.

According to another embodiment of the present invention, a pharmaceutical composition manufacturing method comprises: providing a low-dose medicinal active ingredient and an anti-adhesive agent, wherein the weight ratio of the anti-adhesive agent to the low-dose medicinal active ingredient is 0.5-20, and the anti-adhesive agent Including cerium oxide, talc, cellulose disintegrating agent, hydrophobic disintegrating agent or a combination thereof; uniformly dispersing low-dose pharmaceutically active ingredient and anti-adhesive agent to obtain a first mixture; uniformly dispersing the first mixture and pharmaceutically acceptable An excipient to obtain a second mixture; a granulation step of the second mixture to obtain an active ingredient granule; and the active ingredient granules are tableted or filled into a capsule to obtain a pharmaceutical composition, wherein the pharmaceutically active ingredient occupies the pharmaceutical The composition is about 0.25-5% by weight. .

The above and other aspects, features and advantages of the present invention will become more apparent from the description of the appended claims.

According to an embodiment, the present invention provides a pharmaceutical composition comprising: a low dose of a pharmaceutically active ingredient, an anti-adhesive agent, and a pharmaceutically acceptable excipient. The pharmaceutically active ingredient comprises from about 0.25 to 5% by weight of the pharmaceutical composition. The medicinal active ingredient is uniformly dispersed in the anti-adhesive agent, and the weight ratio of the anti-adhesive agent to the pharmaceutically active ingredient is 0.5-20, and the anti-adhesive agent comprises cerium oxide, talc, cellulose, a hydrophobic disintegrating agent or a combination thereof.

The present invention relates to pharmaceutical compositions for low-dose pharmaceutically active substances, such as Antequavi, which can be administered orally to treat hepatitis B virus infection. The anti-adhesive component of the excipient of the invention has the function of preventing the main component and the excipient and/or preventing the main component itself from generating an electrostatic force, and the agglomeration phenomenon is obtained by uniformly dispersing the Anteccarb in the anti-adhesive agent. The adsorption and electrostatic forces of Tekawi are such that Anteccarb is uniformly dispersed in the powder and subsequently subjected to a granulation step for optimum release.

Referring to FIG. 1, the preparation method of the pharmaceutical composition of the present invention comprises the step S1, providing an anti-adhesive agent and a low-dose medicinal active substance such as Antecvir, wherein the weight ratio of the anti-adhesive agent to the Antecvir is 0.5-20. The amount of Antecavi can range from 0.1 to 1.0 mg. The anti-adhesive agent can be cerium oxide, talc, cellulose, a hydrophobic disintegrating agent, or a combination thereof. For example, cerium oxide may be commercially available Aerosil 200 UC, Adsolider 101; cellulose disintegrating agent may be carboxymethyl cellulose or crystalline cellulose (Avicel); hydrophobic disintegrating agent may be crosslinked polyvinylpyrrolidone Or croscarmellose sodium (Sodium Croscarmellose).

In one embodiment, the anti-adhesive agent used in the present invention is cerium oxide.

The pharmaceutical compositions of the invention for administration can be formulated in any suitable manner. For example, the composition for oral administration can be in the form of a tablet, capsule, granule or powder.

The above formulations may include a pharmaceutically acceptable excipient, and the excipients of the present invention may include a binder, a disintegrating agent, a filler, a lubricant, or a combination thereof.

The binder material is preferably a polymer material having a high viscosity. Suitable materials include Povidone, Methyl cellulose, Carboxymethylcellulose, Hydroxypropyl Methyl Cellulose, Hydroxypropylcellulose, Hydroxyethyl Cellulose, gelatin, Gua gum and Xanthan gum, and mixtures thereof, are preferably polyvinylpyrrolidone. Preferably, the binder material is present in the final composition from from about 0.01% to about 10% by weight of the total composition.

A filler is a medically acceptable substance that can be easily spray coated without prolonged agglomeration. Suitable materials include lactose, microcrystalline cellulose, calcium phosphate, Dextrin, Glucose, Succinate dextran, Mannose. And sorbitol (Sorbitol) and sucrose (Sucrose) and mixtures thereof, preferably lactose and microcrystalline cellulose and mixtures thereof.

The disintegrating agent is comprised of from about 20 wt% to about 50 wt% of the total composition included Preferred in the final composition. Suitable disintegrating agents include Crospovidone, Croscarmellose sodium, Sodium starch glycolate, Pregelatinized Starch, and Corn Starch ( Com starch) and its mixture are preferably crosslinked polyvinylpyrrolidone.

The lubricant is preferably included in the final composition from from about 0.1 to about 5 wt% of the total composition. Suitable lubricants include Magnesium Stearate, Stearic acid, Sodium octadecyl fumarate, and Sodium lauryl sulfate, with magnesium stearate. Preferably.

The invention is also applicable to sustained release formulations. In addition, the low-dose pharmaceutically active substance pharmaceutical composition of the present invention can also be applied to other pharmaceutically active agents or agents suitable for oral administration to form a low-dose pharmaceutically active substance pharmaceutical composition of one or more other pharmaceutically active agents, and finally Reconstitute a single tablet or capsule.

Referring to FIG. 1, in one embodiment, the method for preparing a pharmaceutical composition of the present invention comprises the step S1 of providing an anti-adhesive agent and Antecvir, wherein the weight ratio of the anti-adhesive agent to the Antecvir is 0.5-20. Next, in step S2, the Antecvir and the anti-adherent are uniformly dispersed to obtain a first mixture. For example, the composition is prepared by first screening Anteccarb with an anti-adhesive ceria to uniformly disperse Antecavi, and then adding other excipients to sift together. In addition, the powder can be agitated in a mechanical (high shear) mixer to provide good uniformity of the powder. Next, in step S3, the first mixture and the excipient are uniformly dispersed to form a second mixture, and the step of uniformly dispersing is as described above. Next, a granulation step is carried out in step S4, and the binder forming solution is sprayed or air-flowed onto the powder to form granules. The wet granules are transferred to a desiccator, or the solvent is removed at elevated temperatures using a tray dryer or a suitable dryer such as a fluid bed dryer. After drying, the granules are mixed with other ingredients of the pharmaceutical composition, such as disintegrating agents and/or lubricants. The resulting granule powder is then compressed into tablets or filled into capsules in step S5. With the above formulation and process, it is possible to avoid the adsorption of other substances by Antecavi and to minimize the loss of Antecavi during subsequent processing.

In particular, in an embodiment. In the granulation step, the prepared powder is placed in a container having a fine mesh screen at the bottom, and the gas flow is adjusted to keep the rotation speed of the powder constant and the flow dynamics normal. The powder is maintained at a temperature equilibrium of from about 30 ° C to about 40 ° C. A solution containing the binder material maintained at a temperature of from about 25 ° C to about 75 ° C is sprayed onto the mixture powder containing Antecella at a controlled rate and atomization pressure (0 to 2 bar) to obtain Granules formed by Antecavi with other excipients.

In the above granulation step, the solvent which preferably dissolves the binder is water and pH-adjusted water. Suitable temperatures are then from about 35° to about 60°C.

Further, for the purpose of easy administration, the obtained tablet can be coated with a film. Suitable for polymer coatings, pigments, plasticizers, solvents, etc. for film coatings. Suitable coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, and the like. The film coating may include a polyethylene glycol (Polyethylene Glycol) as a plasticizer. Additional plasticizers such as Diethyl citrate and Diethyl citrate may also be included in the film coating composition. Suitable solubilizing agents include polyoxyethylene xanthophylls fatty acid esters, particularly polysorbate 80 (Tween 80). Suitable pigments include titanium dioxide and various iron oxides. The components of the coating composition are dispersed in a suitable solvent, preferably water. The coating composition can be applied to a tablet using well known disc coating or spray coating techniques.

The following examples illustrate pharmaceutical compositions of the low dose entecavir exemplified in the present invention. Examples 1-3 were prepared using the above procedure to prepare a tablet containing 0.5 mg of entecavir.

Referring to Figure 2 together, there is shown a dissolution profile of Examples 1-3 of the present invention at pH = 1.2, wherein Examples 1 and 2 are Antecoxi tablets which are not protected with an anti-adhesion ceria, and Example 3 is Anteccarb tablet with anti-adhesion cerium oxide protection. It can be seen from the experimental data that the dissolution curve of Example 3 with anti-adhesion ceria protection is better than that of Examples 1 and 2, and is similar to the dissolution curve of the commercially available drug, and the data in Table 4 is known as Example 3 and The uniformity of the content of the commercially available products is similar, so that the anti-adhesion cerium oxide protects the stability of the entecavir.

In summary, the present invention can remove the adsorption and electrostatic force of Antecvir by an anti-adhesive agent, thereby preparing a pharmaceutical composition containing the low-dose active substance Antecavir and improving the stability of Antecwei, thereby effectively Treatment of hepatitis B virus.

The embodiments described above are only intended to illustrate the technical idea and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the contents of the present invention and to implement the present invention. That is, the equivalent variations or modifications made by the spirit of the present invention should still be included in the scope of the present invention.

S1-S5‧‧‧ Manufacturing steps of pharmaceutical compositions

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a flow chart showing the preparation method of the pharmaceutical composition of the present invention; and Fig. 2 is a line graph showing the dissolution curve of the inventive examples 1-3 at pH = 1.2.

S1-S5‧‧‧ Manufacturing steps of pharmaceutical compositions

Claims (19)

A pharmaceutical composition comprising: a low dose of one pharmaceutically active ingredient, wherein the pharmaceutically active ingredient comprises about 0.25-5% by weight of the pharmaceutical composition; an anti-adhesive agent, wherein the medicinal active ingredient is uniformly dispersed in the anti-adhesive The weight ratio of the anti-adhesive agent to the pharmaceutically active ingredient is 0.5-20, and the anti-adhesive agent comprises ceria, talc, cellulose, a hydrophobic disintegrating agent or a combination thereof; and a pharmaceutically acceptable one Formulation. The pharmaceutical composition according to claim 1, wherein the anti-adhesive agent is cerium oxide. The pharmaceutical composition according to claim 1, wherein the cellulose comprises carboxymethylcellulose, microcrystalline cellulose or a combination thereof, and the hydrophobic disintegrating agent comprises crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose Sodium or a combination thereof. The pharmaceutical composition according to claim 1, wherein the excipient comprises a disintegrating agent, a binder, a filler, a lubricant or a combination thereof. The pharmaceutical composition according to claim 4, wherein the binder comprises polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose , gelatin, guar gum, xanthan gum or a combination thereof. The pharmaceutical composition according to claim 4, wherein the filler comprises lactose, microcrystalline cellulose, calcium phosphate, dextrin, glucose, dextran ester, mannitol, sorbitol, sucrose or a combination thereof. The agent comprises magnesium stearate, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate or a combination thereof, and the disintegrating agent comprises gram-crosslinked polyvinylpyrrolidone, Cross-linked sodium carboxymethylcellulose, sodium starch glycolate, pregelatinized starch, corn starch or a combination thereof. The pharmaceutical composition according to claim 1 of the patent application is composed of the following components: 0.25-5% low-dose pharmaceutically active ingredient; 1-3% cerium oxide; and the excipient comprising 25.0-45.0% lactose Monohydrate, 10.0-27.5% microcrystalline cellulose, 10.0-30.0% crosslinked polyvinylpyrrolidone, 15.0-35.0% croscarmellose sodium, 0.5-5% polyvinylpyrrolidone, and 0.2-2% hard Magnesium citrate wherein the above percentages are based on weight/weight. The pharmaceutical composition according to claim 1 of the patent application is composed of the following components: 0.25-5% low-dose pharmaceutically active ingredient; 1-3% cerium oxide; and the excipient, which contains 30.0-40.0% lactose Monohydrate, 13.5-23.5% microcrystalline cellulose, 15.0-25.0% crosslinked polyvinylpyrrolidone, 18.0-30.0% croscarmellose sodium, 0.5-3% polyvinylpyrrolidone, and 0.2-2% hard Magnesium citrate wherein the above percentages are based on weight/weight. The pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient is Antecavi. The pharmaceutical composition according to claim 9 of the patent application is composed of the following components: 0.25-5% Antecvir; 1-3% cerium oxide; and the excipient comprising 25.0-45.0% lactose single Hydrate, 10.0-27.5% microcrystalline fiber Wervin, 10.0-30.0% cross-linked polyvinylpyrrolidone, 15.0-35.0% croscarmellose sodium, 0.5-5% polyvinylpyrrolidone, and 0.2-2% magnesium stearate, wherein the above percentage is by weight / weight is the benchmark. The pharmaceutical composition according to claim 9 of the patent application is composed of the following components: 0.25-5% Antecvir; 1-3% cerium oxide; and the excipient comprising 30.0-40.0% lactose single Hydrate, 13.5-23.5% microcrystalline cellulose, 15.0-25.0% crosslinked polyvinylpyrrolidone, 18.0-30.0% croscarmellose sodium, 0.5-3% polyvinylpyrrolidone, and 0.2-2% stearin Magnesium sulphate, wherein the above percentages are based on weight/weight. The pharmaceutical composition according to claim 1 of the patent application is a tablet, a powder or a capsule. A pharmaceutical composition manufacturing method comprising: providing a low-dose medicinal active ingredient and an anti-adhesive agent, wherein the anti-adhesive agent and the low-dose pharmaceutically active ingredient are in a weight ratio of 0.5-20, and the anti-adhesive agent comprises cerium oxide, a talc powder, a cellulose disintegrating agent, a hydrophobic disintegrating agent or a combination thereof; uniformly dispersing a low-dose medicinal active ingredient and the anti-adhesive agent to obtain a first mixture; uniformly dispersing the first mixture and one of pharmaceutically acceptable forms To obtain a second mixture; subjecting the second mixture to a granulation step to obtain an active ingredient granule; and pulverizing or filling the active ingredient granules to obtain the pharmaceutical composition, wherein the medicinal active ingredient accounts for The pharmaceutical composition is about 0.25-5% by weight. The pharmaceutical composition manufacturing method according to claim 13, wherein the pharmaceutically active ingredient is Antecavi. The method for producing a pharmaceutical composition according to claim 13 or 14, wherein the granulating step is achieved by spraying a solution containing one of the binders, wherein the binder comprises polyvinylpyrrolidone, methylcellulose, Hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum or a combination thereof. The method for producing a pharmaceutical composition according to claim 13 or 14, wherein the cellulose comprises carboxymethylcellulose, crystalline cellulose or a combination thereof, the hydrophobic disintegrating agent comprising crosslinked polyvinylpyrrolidone, cross-linked carboxylate Sodium methylcellulose or a combination thereof. The pharmaceutical composition manufacturing method according to claim 13 or 14, wherein the anti-adhesive agent is cerium oxide. The pharmaceutical composition manufacturing method according to claim 13 or 14, wherein the excipient further comprises a disintegrating agent, a filler, a lubricant or a combination thereof. The pharmaceutical composition manufacturing method according to claim 18, wherein the filler comprises lactose, microcrystalline cellulose, calcium phosphate, dextrin, glucose, dextran ester, mannitol, sorbitol, sucrose or a combination thereof. The lubricant comprises magnesium stearate, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate or a combination thereof, and the disintegrating agent comprises crosslinked polyvinylpyrrolidone, croscarmellose sodium, starch Sodium glycolate, pregelatinized starch, corn starch or a combination thereof.