CN107714676B

CN107714676B - Entecavir oral instant film agent and preparation method thereof

Info

Publication number: CN107714676B
Application number: CN201711027198.2A
Authority: CN
Inventors: 曹青日; 魏腾
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2017-10-27
Filing date: 2017-10-27
Publication date: 2020-05-15
Anticipated expiration: 2037-10-27
Also published as: CN107714676A

Abstract

The invention relates to an entecavir oral instant film agent, which comprises the following components in parts by mass based on the total weight: 0.05 to 15 percent of entecavir; 55-90% of polyvinyl alcohol/polyethylene glycol graft copolymer; 5-15% of glycerol plasticizer; 0.5 to 15 percent of sodium alginate disintegrating agent. The invention also provides a preparation method thereof, which comprises the following steps: (1) uniformly mixing the polyvinyl alcohol/polyethylene glycol graft copolymer with water to obtain polymer gel; (2) adding entecavir into the polymer gel, uniformly mixing, and then adding a plasticizer and a sodium alginate disintegrating agent to obtain a medicine-containing solution; (3) degassing the medicine-containing solution, coating the degassed medicine-containing solution on a base material, drying the base material at 40-60 ℃, and cutting the base material to obtain the entecavir oral instant film agent. The oral instant film agent can obviously accelerate the disintegration time limit of the film agent, solves the defect that most of the oral solid preparations at present need water for taking, does not delay the medicine taking time under the condition of no water resource, and improves the medication compliance of patients.

Description

Entecavir oral instant film agent and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to an entecavir oral instant film agent and a preparation method thereof.

Background

Entecavir is cyclopentyl guanine nucleoside analogue, is an oral nucleoside medicament for selectively resisting Hepatitis B Virus (HBV), and has the following structural formula:

because oral formulations have long dissolution time and low dissolution rates, difficulties exist for patients requiring onset of action within a short time (1 hour or half hour). In addition, the conventional tablet also has problems of oral administration requiring simultaneous administration with water, low compliance, etc., and therefore, it is necessary to develop an administration form which is convenient for oral administration and is immediate-release.

The oral solid quick-release preparation comprises orally disintegrating tablet, sublingual tablet, dispersible tablet and oral instant membrane (RDF). Wherein the RDF is a preparation prepared by dispersing a certain amount of chemicals or effective components of Chinese medicinal extract in film-forming material. Such oral immediate release dosage forms are of great importance in the pharmaceutical industry. It can disintegrate in saliva within one minute, release the active ingredient of the drug, and be absorbed through the oral mucosa. The oral film agent can be prepared by improving the prescription, and the medicine can be quickly dissolved in the gastrointestinal tract after being swallowed. RDF overcomes the defect that most oral solid preparations need water for taking at present, and the medicine taking time is not delayed under the condition of no water resource; provides a proper medicine taking way for some patients with aggravated nausea and vomiting after drinking water; provides a safe and reliable medication way for the old, the seriously ill patients and the infants, and improves the compliance of the patients.

RDF has the advantages of rapid disintegration, rapid drug release, no need of drinking water, and the like, as well as other quick-release dosage forms such as orally disintegrating tablets, sublingual tablets, dispersible tablets, and the like. In addition, the RDF overcomes the defects of complex preparation process and large friability of orally disintegrating tablets, sublingual tablets and dispersible tablets, has simple preparation process, no friability and convenient carrying, is popular with people and has strong competitiveness in the market.

At home and abroad, no report for preparing the entecavir into the oral instant film preparation exists so far, so that the research for preparing the entecavir into the oral instant film preparation is very important and has a far-reaching significance.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide an entecavir oral instant film agent and a preparation method thereof, so as to realize rapid disintegration and rapid drug release, be convenient to carry and improve the compliance of patients.

The invention provides an entecavir oral instant film agent, which comprises the following components in parts by mass based on the total weight of the entecavir oral instant film agent: 0.05 to 15 percent of entecavir; 55-90% of polyvinyl alcohol/polyethylene glycol graft copolymer; 5-15% of glycerol plasticizer; 0.5 to 15 percent of sodium alginate disintegrating agent.

Further, entecavir is selected from one of its polymorphic forms, namely the monohydrate crystalline form.

Furthermore, the entecavir oral instant film agent also comprises auxiliary materials, wherein the auxiliary materials are one or more of coloring agent, suspending agent and flavoring agent.

Further, the mass fraction of the colorant is 0.5-10%; the coloring agent is titanium dioxide and/or indigo. Preferably, the colorant is titanium dioxide.

Further, the mass fraction of the suspending agent is 0.5-10%; the suspending agent is one or more of microcrystalline cellulose and sodium carboxymethylcellulose mixture, acacia and tragacanth. Preferably, the suspending agent is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, the viscosity of which is 65mpa.s, wherein the mass fraction of sodium carboxymethylcellulose is 11%.

Further, the mass fraction of the flavoring agent is 0.1-10%; the correctant is one or more of mannitol, sorbitol and stevioside. Preferably, the flavoring agent is mannitol.

Further, on the basis of the total weight of the entecavir oral instant film, the entecavir oral instant film comprises the following components in parts by mass: 0.05 to 15 percent of entecavir; 55-90% of polyvinyl alcohol/polyethylene glycol graft copolymer; 5-15% of glycerol plasticizer; sodium alginate disintegrating agent 0.5-15%; 0.5 to 10 percent of colorant; 0.5 to 10 percent of suspending agent; 0.1-10% of flavoring agent.

Further, on the basis of the total weight of the entecavir oral instant film, the entecavir oral instant film comprises the following components in parts by mass: 1.2% of entecavir; 71.4 percent of polyvinyl alcohol/polyethylene glycol graft copolymer; 10.7% of glycerol plasticizer; 14.3 percent of sodium alginate disintegrating agent; 1.2% of a coloring agent; 1.2 percent of suspending agent.

Furthermore, the polyvinyl alcohol/polyethylene glycol graft copolymer contains polyvinyl alcohol and polyethylene glycol chain segments at the same time. The polyvinyl alcohol in the polyvinyl alcohol/polyethylene glycol graft copolymer accounts for 75% of the total weight of the graft copolymer, and the polyethylene glycol accounts for 25% of the total weight of the graft copolymer.

Further, the molecular weight of the polyvinyl alcohol/polyethylene glycol graft copolymer was 45000 daltons.

The invention also provides a preparation method of the entecavir oral instant film agent, which comprises the following steps:

(1) uniformly mixing the polyvinyl alcohol/polyethylene glycol graft copolymer with water to obtain polymer gel;

(2) adding entecavir into the polymer gel, uniformly mixing, and then adding a glycerol plasticizer and a sodium alginate disintegrating agent to obtain a medicine-containing solution;

(3) degassing the medicine-containing solution, coating the degassed medicine-containing solution on a base material, drying the base material at 40-60 ℃, and cutting the base material to obtain the entecavir oral instant film agent.

Further, the water is purified water or deionized water. Purified water is preferred, which can ensure that the oral instant film agent has the strength and toughness suitable for cutting and subpackaging. Water is used as a solvent and does not appear in the final entecavir oral instant film.

Further, before the step (3), a step of adding auxiliary materials is also included, wherein the auxiliary materials are one or more of coloring agents, suspending agents and flavoring agents.

Further, in the step (3), the substrate is a stainless steel plate or a plastic plate.

The invention selects the hydrophilic entecavir as the medicinal component of the oral instant film agent, and the polyvinyl alcohol/polyethylene glycol graft copolymer as the carrier, which has the advantages of good water absorption, no toxicity, no irritation, good film forming property, easy demoulding, etc. Glycerol is hygroscopic and the mixture with water is chemically stable. The glycerol is used as a plasticizer, and the prepared film agent has smooth and transparent surface, relatively good toughness and strength and convenient demoulding. Sodium alginate is used as the disintegrating agent, and the sodium alginate is odorless, tasteless, nontoxic, high in flexibility and hygroscopic; dissolved in water to form a viscous colloidal solution, typically a hydrophilic sol. The prepared film agent has smooth, transparent, tough and tactile sensation surface and is convenient to demould.

By the scheme, the invention at least has the following advantages:

(1) the entecavir oral instant film agent is suitable for being taken in any occasions, does not need water, is convenient to carry, solves the problem of difficulty caused by swallowing dysfunction when a solid preparation is taken orally, and avoids the danger of suffocation caused by respiratory tract obstruction. The oral instant film agent disclosed by the invention is also suitable for patients who drink water and aggravate vomiting, and improves the compliance of the patients.

(2) By optimizing the composition and proportion in the formula of the film agent, the entecavir oral instant film agent prepared from the polyvinyl alcohol/polyethylene glycol graft copolymer, the glycerol plasticizer and the sodium alginate can obviously shorten the disintegration time of the preparation while maintaining excellent mechanical properties, and solves the problem of longer disintegration time of the traditional film agent.

(3) Because the disintegration time limit of the film agent is optimized, the dissolution effect of the medicine is improved, the medicine dosage required for reaching the same medicine effect is reduced, and the raw material cost is saved.

(4) The entecavir oral instant film agent of the invention selects the water-soluble polyvinyl alcohol/polyethylene glycol graft copolymer as the film forming material, and selects the proper plasticizer, disintegrant, other auxiliary materials and the weight proportion thereof, thus preparing the film agent with good disintegration time and mechanical property. The oral instant film agent can obviously accelerate the disintegration time limit of the film agent, solves the defect that most of the oral solid preparations at present need water for taking, does not delay the medicine taking time under the condition of no water resource, and improves the medication compliance of patients.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.

Drawings

FIG. 1 is a graph of the thickness and disintegration time of an entecavir oral fast dissolving film of examples 1-12;

fig. 2 is a graph of the modulus of elasticity and tensile strength of the entecavir oral fast dissolving film of examples 1-12;

fig. 3 is a graph of the percent elongation of the entecavir oral fast dissolving film of examples 1-12;

FIG. 4 is a graph showing the dissolution rate of the entecavir oral instant film and the original drug in example 7 at pH 1.0;

FIG. 5 is a graph showing the dissolution rate of the entecavir oral instant film and the original drug substance in example 7 at pH 4.5;

FIG. 6 is a graph showing the dissolution rate of the entecavir oral instant film and the original drug substance in example 7 at pH 6.8;

fig. 7 is a dissolution diagram of the entecavir oral instant film and the original ground drug in example 7 under the condition of pH 7.4.

Detailed Description

The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1

The invention relates to an entecavir oral instant film agent, which comprises the following components in percentage by weight:

wherein, the polyvinyl alcohol in the polyvinyl alcohol/polyethylene glycol graft copolymer accounts for 75 percent of the total weight of the graft copolymer, the polyethylene glycol accounts for 25 percent of the total weight of the graft copolymer, and the molecular weight of the polyvinyl alcohol/polyethylene glycol graft copolymer is 45000 Da.

The preparation method of the entecavir oral instant film agent comprises the following steps:

the polyvinyl alcohol/polyethylene glycol graft copolymer with the mass is added into 10mL of pure water under the stirring state, and the mixture is stirred and dissolved to obtain polymer gel. Then adding entecavir, glycerol and sodium alginate, and stirring to obtain a solution containing medicine. Standing or ultrasonically removing bubbles, uniformly coating on a stainless steel plate of 2cm × 15cm, and air-blowing and heating at 40-60 deg.C for 2 hr. Demoulding and cutting to obtain the entecavir oral instant film agent. It is white and transparent, and has thin film thickness, difficult demoulding and local wrinkle.

Example 2

An entecavir oral fast dissolving film was prepared according to the method of example 1. The prepared film agent is transparent, the film thickness is moderate, the demoulding is convenient, and the local wrinkle phenomenon exists.

Example 3

Example 4

the polyvinyl alcohol/polyethylene glycol graft copolymer with the mass is added into 10mL of pure water under the stirring state, and the mixture is stirred and dissolved to obtain polymer gel. Then adding entecavir, glycerol, sodium alginate and titanium dioxide, and stirring uniformly to obtain a medicine-containing solution. Standing or ultrasonically removing bubbles, uniformly coating on a stainless steel plate of 2cm × 15cm, and air-blowing and heating at 40-60 deg.C for 2 hr. Demoulding and cutting to obtain the entecavir oral instant film agent. It is white, has moderate thickness and has wrinkles on the local part.

Example 5

An entecavir oral fast dissolving film was prepared according to the method of example 4. The prepared film agent is white, has moderate thickness, is not easy to demould and has the phenomenon of local wrinkles.

Example 6

An entecavir oral fast dissolving film was prepared according to the method of example 4. The prepared film agent is white, thick, difficult to demould and has wrinkles on the local part.

Example 7

wherein, the polyvinyl alcohol in the polyvinyl alcohol/polyethylene glycol graft copolymer accounts for 75 percent of the total weight of the graft copolymer, the polyethylene glycol accounts for 25 percent of the total weight of the graft copolymer, and the molecular weight of the polyvinyl alcohol/polyethylene glycol graft copolymer is 45000 Da. The viscosity of the microcrystalline cellulose-sodium carboxymethylcellulose mixture is 65mPa.s, wherein the mass fraction of the sodium carboxymethylcellulose is 11%.

the polyvinyl alcohol/polyethylene glycol graft copolymer with the mass is added into 10mL of pure water under the stirring state, and the mixture is stirred and dissolved to obtain polymer gel. Then adding entecavir, glycerol, sodium alginate, titanium dioxide and microcrystalline cellulose-sodium carboxymethylcellulose mixture, and stirring to obtain a solution containing medicine. Standing or ultrasonically removing bubbles, uniformly coating on a stainless steel plate of 2cm × 15cm, and air-blowing and heating at 40-60 deg.C for 2 hr. Demoulding and cutting to obtain the entecavir oral instant film agent. It is white, has moderate thickness, is convenient for demoulding and has no obvious microcrystalline cellulose (MCC) particles.

Example 8

An entecavir oral fast dissolving film was prepared according to the method of example 7. The prepared film agent is white, the film is thick, the demoulding is convenient, and the local wrinkling phenomenon and MCC particles exist.

Example 9

Example 10

the polyvinyl alcohol/polyethylene glycol graft copolymer with the mass is added into 10mL of pure water under the stirring state, and the mixture is stirred and dissolved to obtain polymer gel. Then adding entecavir, glycerol, sodium alginate, titanium dioxide, microcrystalline cellulose-sodium carboxymethylcellulose mixture and mannitol, and stirring to obtain a medicine-containing solution. Standing or ultrasonically removing bubbles, uniformly coating on a stainless steel plate of 2cm × 15cm, and air-blowing and heating at 40-60 deg.C for 2 hr. Demoulding and cutting to obtain the entecavir oral instant film agent. It is white, the film is hard and thick, the demoulding is convenient, and the local wrinkle phenomenon exists.

Example 11

An entecavir oral fast dissolving film was prepared according to the method of example 10. The prepared film agent is white, the film is thick, the demoulding is convenient, and the local wrinkle phenomenon exists.

Example 12

An entecavir oral fast dissolving film was prepared according to the method of example 10. The prepared film agent is white, thick, difficult to demould and has wrinkles on the local part.

Example 13

The disintegration time of the oral instant films in examples 1-12 was determined by the disintegration time measurement method of the oral instant films, which specifically was as follows:

in a drug dissolution instrument, 500mL of purified water is added into a 1000mL dissolution cup, a thermostatic water bath at 37 ℃ is carried out, the rotating speed of a stirring paddle is adjusted to 100r/min, a test film is placed into a disintegration basket and placed into the water bath for timing, and the time for dissolving the film agent is recorded. In this experiment, 3 blocks of the instant oral film prepared in each example were measured, each block size being 2cm × 3cm, and the mean of the three measurements was taken as the disintegration time of the film.

The results are shown in FIG. 1. As can be seen from the figure, under the condition of adding the main drug, the dosage of the carrier polyvinyl alcohol/polyethylene glycol graft copolymer, the plasticizer glycerin, the disintegrating agent sodium alginate, the coloring agent titanium dioxide, the suspending agent microcrystalline cellulose-sodium carboxymethylcellulose mixture and the flavoring agent mannitol in the film agent are changed, and the dosage has influence on the thickness and the disintegration time of the film agent; the drug adding product takes polyvinyl alcohol/polyethylene glycol graft copolymer as a carrier, glycerol as a plasticizer, sodium alginate as a disintegrating agent, titanium dioxide as a coloring agent and a microcrystalline cellulose-sodium carboxymethylcellulose mixture as a suspending agent, and the mass ratio of the drug adding product to the carrier is 60: 9: 12: 1: 1: 1, moderate thickness and relatively short disintegration time. Indicating that the film prepared according to the method of the present invention has good instant solubility.

Example 14

The mechanical properties of the films of examples 1 to 12 were evaluated by using an HY-1080 model universal material testing machine. A2 cm by 0.5cm film dosage was placed between two clips 5cm apart. The film was pulled at a speed of 10mm/min by a pulling pliers. The mechanical properties of the instant films such as modulus of Elasticity (EM), Tensile Strength (TS), percent elongation (E%) are calculated as follows:

(1) the elastic modulus is the ratio of the applied stress to the strain force during the elastic deformation phase, and can be calculated by using the following formula:

elastic modulus is applied stress/strain force/cross-sectional area;

(2) the tensile strength is also called strength limit, which means the maximum stress value borne by the material before breaking, and the calculation formula is as follows:

tensile strength-applied stress/cross-sectional area;

(3) percent elongation was calculated by the following formula:

percent elongation-length increase/original length x 100

The mechanical properties of the films obtained in examples 1 to 12 were measured by this method, and the results are shown in FIGS. 2 and 3. As can be seen from the figure, the modulus of elasticity of the film is between 13 and 57MPa, the tensile strength is between 1 and 4MPa, and the percent elongation is within 100 percent. The elastic modulus is reduced, the percentage elongation is increased, the flexibility is enhanced, and the processing and the use are more suitable.

Example 15

Taking the entecavir oral instant film prepared in example 7, cutting 3 films with the size of 2cm × 3cm, taking the entecavir tablets (0.5mg × 2) in the original research as a reference, according to a device of a dissolution determination method (XC second method in appendix II of the second part of the 2010 edition of Chinese pharmacopoeia), respectively taking 500mL of PBS (pH1.0, pH4.5, pH6.8, pH7.4) as dissolution media, respectively, performing in-vitro release of the medicine at the temperature of 37 ± 0.5 ℃ and the rotation speed of 100r/min, respectively sampling 2mL of the solution as a test solution in 5, 10, 15, 30, 60, 120min, and simultaneously supplementing 2mL of the dissolution media with the same temperature and the same amount. The test solution is centrifuged at 10000r/min for 15 minutes, and then HPLC analysis is carried out, the peak area is recorded, and the dissolution rate of the drug is calculated.

The results are shown in fig. 4-7, and it can be seen from the graphs that the dissolution curves of the entecavir oral instant film agent of the invention and the original medicine are basically consistent.

Example 16

example 17

example 17

the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims

1. The entecavir oral instant film agent is characterized by comprising the following components in parts by mass based on the total weight of the entecavir oral instant film agent: 0.05 to 15 percent of entecavir; 55-90% of polyvinyl alcohol/polyethylene glycol graft copolymer; 5-15% of glycerol plasticizer; sodium alginate disintegrating agent 0.5-15%; 0.5 to 10 percent of colorant; 0.5 to 10 percent of suspending agent; 0.1-10% of flavoring agent; the coloring agent is titanium dioxide and/or indigo; in the polyvinyl alcohol/polyethylene glycol graft copolymer, polyvinyl alcohol accounts for 75% of the total weight of the graft copolymer, and polyethylene glycol accounts for 25% of the total weight of the graft copolymer; the suspending agent is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose; the mass fraction of the sodium carboxymethyl cellulose in the microcrystalline cellulose-sodium carboxymethyl cellulose mixture is 11%.

2. The entecavir oral fast dissolving film of claim 1, wherein: the mass fraction of the flavoring agent is 0.1-10%; the correctant is one or more of mannitol, sorbitol and stevioside.

3. The entecavir oral fast dissolving film of claim 1, wherein: the molecular weight of the polyvinyl alcohol/polyethylene glycol graft copolymer is 45000 daltons.

4. A method of preparing an entecavir oral fast dissolving film according to any one of claims 1-3, comprising the steps of:

(3) and degassing the medicine-containing solution, coating the degassed medicine-containing solution on a base material, and drying at 40-60 ℃ to obtain the entecavir oral instant film agent.

5. The method for preparing an entecavir oral instant film agent according to claim 4, wherein the method comprises the following steps: before the step (3), the method also comprises a step of adding auxiliary materials, wherein the auxiliary materials are one or more of coloring agents, suspending agents and flavoring agents.