CN113750058B

CN113750058B - Phloroglucinol freeze-dried orally disintegrating tablet and preparation method thereof

Info

Publication number: CN113750058B
Application number: CN202010484076.1A
Authority: CN
Inventors: 张勇; 张轶; 郑顺利
Original assignee: Beijing Jiuneng Tianyuan Technology Co ltd
Current assignee: Beijing Jiuneng Tianyuan Technology Co ltd
Priority date: 2020-06-01
Filing date: 2020-06-01
Publication date: 2023-07-04
Anticipated expiration: 2040-06-01
Also published as: CN113750058A

Abstract

The invention belongs to the technical field of medicines, and discloses a phloroglucinol freeze-dried orally disintegrating tablet and a preparation method thereof. The phloroglucinol freeze-dried orally disintegrating tablet comprises phloroglucinol, a freeze-drying protective agent, a disintegrating agent and other medicinal excipients. Wherein the disintegrant is hydroxypropyl-beta-cyclodextrin (HP-beta-CD), the content of the disintegrant is less than 15% and the content of the phloroglucinol is more than 70% by weight of the total tablet. The orally disintegrating tablet is prepared by adopting a freeze-drying flash release technology, has high effective drug loading quantity, moderate tablet weight and difficult breaking, can be dissolved without water on the premise of ensuring the specification of the preparation to be 80mg, and is particularly suitable for the old, children, dysphagia patients and water-taking inconveniences.

Description

Phloroglucinol freeze-dried orally disintegrating tablet and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a phloroglucinol freeze-dried orally disintegrating tablet and a preparation method thereof.

Background

Phloroglucinol (trade name: spafen) is a smooth muscle spasmolytic, and is mainly used for acute spasmodic pain caused by digestive system and biliary tract dysfunction; acute spasmodic urinary tract, bladder, renal colic; gynecological spasmodic pain. Compared with other smooth muscle spasmolytics, the biggest characteristic is that there is little anaphylactic reaction, such as drug eruption, urticaria and the like, and meanwhile, the changes of blood pressure and heart rate are not caused.

The phloroglucinol has been marketed abroad in two dosage forms, namely oral lyophilized tablet and injection. Wherein, the phloroglucinol oral freeze-dried tablet is more convenient to take, the tablet is taken by an adult 2 times per day, the tablet can be taken repeatedly for 2-3 times per day, and the usage is that the freeze-dried tablet is dissolved in small cup of water for drinking or is taken sublingually. The phloroglucinol injection and the oral freeze-dried tablet of the large pharmaceutical factory Lafon in France are approved in 2001 in China, and the phloroglucinol injection produced in China is approved to be marketed later. However, only the phloroglucinol injection simulated by Wu Hanren Fu, wanbond pharmacy, the Hubei noon pharmacy, the Shandong New era pharmacy and Nanjing Hengsheng pharmacy is sold in China, and no oral freeze-dried tablet simulated by more convenient clinical use and more requirements is marketed.

For the above reasons, some pharmaceutical research institutions or pharmaceutical enterprises-like phloroglucinol oral tablets are also slightly researched at present. For example, chinese patent application CN200710172518.3 discloses a phloroglucinol orally disintegrating tablet and a preparation method thereof, the phloroglucinol orally disintegrating tablet has high hardness, simple preparation process and remarkable curative effect, and can be rapidly disintegrated in the mouth at the time of fastest contact with saliva of less than 10 seconds, and is convenient for patients to take, but the content of phloroglucinol is only 15-30% by weight of the total weight of the tablet. Although the auxiliary materials which meet the pharmaceutical standard are not rejected in the pharmaceutical preparation, the auxiliary materials are used as inert components in the medicines, and are safe in most cases, some adverse reactions of the medicines are caused by the auxiliary materials, so that unnecessary auxiliary materials are reduced as much as possible, the types of the auxiliary materials are reduced, the effective drug loading rate is improved, the safe drug use is certainly facilitated, and the drug cost can be further reduced on the premise that the drug loading rates are the same. Some chinese patent applications have drawbacks, although they have increased the drug loading of phloroglucinol, for example, the phloroglucinol oral tablets disclosed in chinese patent applications CN201610244856.2, CN201310660189.2, CN201310715760.6, CN200910273377.3 also have the problem of low content of phloroglucinol (up to about 40%), and the former has only about 80% of the dissolution in 20 min. For example, chinese patent application CN200610167502.9 provides an orally disintegrating tablet of phloroglucinol, which is prepared by adding a disintegrant, a filler, a lubricant, a flavoring agent, an adhesive and an effervescent agent into phloroglucinol as an active ingredient, wherein the dosage of the disintegrant is relatively large, up to 20%; there are also some applications such as CN201210587328.9, CN200910273377.3 where an antioxidant or stabilizer is required to be added to the phloroglucinol oral formulation.

Disclosure of Invention

The invention aims to overcome the defects of the background technology and provide the phloroglucinol freeze-dried orally disintegrating tablet with the effective drug loading up to 70 percent, which is prepared by adopting a freeze-drying flash-release technology, and can be dissolved without water and an inlet on the premise of ensuring the preparation specification of 80mg, thereby solving the problem of inconvenient medication of patients.

In order to achieve the aim of the invention, the phloroglucinol freeze-dried orally disintegrating tablet comprises phloroglucinol, a freeze-drying protective agent, a disintegrating agent and other medicinal excipients, wherein the disintegrating agent is hydroxypropyl-beta-cyclodextrin (HP-beta-CD), the content of the disintegrating agent is lower than 15 percent, and the content of the phloroglucinol is higher than 70 percent according to the total weight of the tablet.

In some embodiments of the invention, the phloroglucinol of the present invention is phloroglucinol dihydrate.

Preferably, in some embodiments of the present invention, the phloroglucinol particle size D90 is less than or equal to 5 μm.

In some embodiments of the invention, the other pharmaceutically acceptable excipients are matrix supports, binders, and sweeteners.

Further, the skeleton supporting agent of the present invention may be an auxiliary material known to those skilled in the art to function as skeleton support in the preparation of orally disintegrating tablets, such as glycine, serine, arginine, mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, dextran, xylose, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminum silicate, or a mixture of the above skeleton supporting agents.

Preferably, in some embodiments of the invention, the skeletal support agent is mannitol.

Further, the binder of the present invention may be a binder known to those skilled in the art in preparing orally disintegrating tablets, such as pullulan, cellulose and its derivatives, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan or a mixture thereof.

Preferably, in some embodiments of the invention, the binder is pullulan.

Further, the sweetener of the present invention may be a sweetener known to those skilled in the art in preparing an oral pharmaceutical formulation, such as sodium cyclamate, acesulfame potassium, sucralose, aspartame, sucrose, sodium saccharin, proteoglycan, glucose, steviosin, stevioside, glycyrrhizin, thaumatin, citric acid, tartaric acid, malic acid, lactic acid, peppermint essence, orange essence, pineapple essence, strawberry essence, lemon essence, juicy peach essence, vanilla essence, cherry essence, grape essence, chocolate essence, or a mixture thereof.

Preferably, in some embodiments of the invention, the sweetener is sucralose.

Further, in some embodiments of the invention, the lyoprotectant is dextran-70.

Further preferably, in some embodiments of the present invention, the phloroglucinol lyophilized orally disintegrating tablet comprises phloroglucinol dihydrate, mannitol, pullulan, dextran-70, sucralose, and hydroxypropyl-beta-cyclodextrin.

More preferably, in some embodiments of the present invention, the phloroglucinol freeze-dried orally disintegrating tablet comprises less than 14% of the disintegrant, more than 74% of the phloroglucinol dihydrate, 0.1 to 0.8% of the pullulan, 2 to 5% of the dextran-70, 0.1 to 1.0% of the sucralose, and 7 to 12% of the mannitol, based on the total weight of the tablet.

In another aspect, the invention also provides a preparation method of the phloroglucinol freeze-dried orally disintegrating tablet, which comprises the following steps:

(1) Preparing a matrix liquid: weighing HP-beta-CD and purified water, placing into a container to prepare a solution, adding the solution into the phloroglucinol subjected to the micro powder treatment, placing the solution into a magnetic stirrer for stirring, adding a freeze-drying protective agent and other medicinal excipients into the solution obtained by stirring, and continuing stirring;

(2) Degassing: shearing the solution obtained in the step (1) uniformly and degassing until no obvious bubbles exist;

(3) Injection molding: injecting the solution degassed in the step (2) into a mold;

(4) And (3) freeze drying: freeze-drying for 1-12 h under the pressure of 10-500 mu bar and the temperature of minus 35-15 ℃ to obtain the phloroglucinol freeze-dried orally disintegrating tablet.

Further, the micro powder treatment is to treat the phloroglucinol micro powder until the particle size D90 is less than or equal to 5 mu m.

Compared with the prior art, the invention has the following advantages:

(1) The phloroglucinol freeze-dried orally disintegrating tablet disclosed by the invention has the advantages that the dosage of auxiliary materials is small, compared with the prior art, the dosage of the disintegrating agent is greatly reduced, the principle of disintegration is that the preparation is disintegrated in the oral cavity through the porous property left after freeze-drying, and the medicine and the auxiliary materials can be rapidly and completely dispersed in saliva, so that the defect that the orally disintegrating preparation prepared by a direct tabletting method and other prior art has a gritty feeling in the oral cavity or the defect that the effective drug loading amount is low is overcome;

(2) The phloroglucinol freeze-dried orally disintegrating tablet is suitable for being prepared by a freeze-drying technology, has low auxiliary material content, stable quality of the tested medicine, controllable impurity content after long-term preservation, basically unchanged content of active ingredients of the medicine, and does not need to additionally add a stabilizer or an antioxidant;

(3) The phloroglucinol freeze-dried orally disintegrating tablet disclosed by the invention has good taste, is convenient to take, can disintegrate or dissolve in saliva without being taken with water, and is especially suitable for the old, children, dysphagia patients and inconvenient water taking patients to take;

(4) The phloroglucinol freeze-dried orally disintegrating tablet provided by the invention is rapidly disintegrated in the mouth, and a considerable part of the phloroglucinol freeze-dried orally disintegrating tablet is absorbed through the oral cavity, so that the effect is rapid, and the first pass effect of the liver is small;

(5) The phloroglucinol freeze-dried orally disintegrating tablet can be rapidly disintegrated and dispersed into fine particles before the medicine reaches the gastrointestinal tract, so that the medicine is distributed in a large area in the gastrointestinal tract, the absorption points are increased, and the local irritation of the medicine to the gastrointestinal tract is reduced;

(6) The preparation prescription process solves the technical problem that the medicine with large medicine carrying capacity (specification: 80 mg) is prepared into orally disintegrating tablets (freeze-dried), breaks through the limitation of the orally disintegrating tablets (freeze-dried) in the aspects of specification and tablet weight, has high effective medicine carrying capacity and moderate tablet weight, and is not easy to break.

Drawings

FIG. 1 is a graph of dissolution of a reference formulation from a phloroglucinol orally disintegrating tablet of lot 191125, wherein the upper gray curve represents the reference formulation and the lower black is the phloroglucinol orally disintegrating tablet of lot 191125 of the present invention, with time/min on the abscissa and dissolution on the ordinate;

fig. 2 is a lyophilization profile in the preparation method of phloroglucinol lyophilized orally disintegrating tablets in accordance with example 1 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It is to be understood that the following description is intended to be illustrative of the invention and not restrictive.

The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

When an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when ranges of "1 to 5" are disclosed, the described ranges should be construed to include ranges of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.

The indefinite articles "a" and "an" preceding an element or component of the invention are not limited to the requirement (i.e. the number of occurrences) of the element or component. Thus, the use of "a" or "an" should be interpreted as including one or at least one, and the singular reference of an element or component includes the plural reference unless the amount clearly dictates otherwise.

Furthermore, the descriptions of the terms "one embodiment," "some embodiments," "examples," "particular examples," or "some examples," etc., described below mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily for the same embodiment or example. The technical features of the respective embodiments of the present invention may be combined with each other as long as they do not collide with each other.

Unless otherwise indicated, the term "rapid release" in the present invention has the meaning commonly used in the art, and the term "rapid release" in the present invention means that the supplement disintegrates in the mouth for less than 10 seconds, preferably less than 5 seconds.

Example 1

A method of preparing the phloroglucinol freeze-dried orally disintegrating tablet, the method comprising the steps of:

(1) Weighing prescribed amount of HP-beta-CD and purified water, placing the solution into a beaker, adding prescribed amount of phloroglucinol (subjected to micro powder treatment, and the particle size D90 is less than or equal to 5 mu m), placing the solution on a magnetic stirrer, and stirring for 1 hour at the rotating speed of 600 r/min;

(2) Adding the freeze-drying protective agent, the framework supporting agent, the binder and the sweetener with the prescription amount into the solution obtained by stirring in the step (1), and continuously stirring for 30min;

(3) Shearing, stirring at 1500r/min for 10min, and degassing until no obvious bubbles exist;

(4) Stirring continuously at 600r/min, transferring a specified volume into a bubble cap, pre-freezing and forming at a low temperature of-40 ℃, and freeze-drying for 1-12 h under the conditions of 10-500 mu bar pressure and-35-15 ℃ to obtain the phloroglucinol freeze-dried orally disintegrating tablet.

In the preparation process of the phloroglucinol freeze-dried orally disintegrating tablet, the influence of the pre-freezing temperature on the appearance of the freeze-dried tablet is larger, and when the temperature is too high, the surface of the prepared freeze-dried tablet is rough; when the temperature is too low, the energy consumption in the industrial production process is higher. In the research of the influence of the pre-freezing time on the freeze-dried tablet, the bubble phenomenon can occur in the drying process when the solution is not frozen too short, and the volume of the freeze-dried tablet can be reduced; when the time is too long, energy waste is caused. In the research of the influence of the freeze-drying process on the freeze-dried tablets, the freeze-drying process has influence on the water content, the formability, the microstructure and the disintegration performance of the freeze-dried tablets. The invention is characterized in that a great amount of experiments prove that the parameters of temperature and vacuum degree in the prefreezing and freeze-drying processes are shown in table 1, and the freeze-drying curve is shown in figure 2.

TABLE 1 parameters of temperature and vacuum during Pre-freezing and freeze drying

Example 2

In the prescription screening process, the inventor finds that the bulk drug is seriously settled and has large tablet weight difference in the liquid preparation process when the bulk drug is not subjected to micro powder treatment. According to years of research and development experience of Qsorb technology, the crude drug is subjected to differential treatment (the grain diameter D90 is less than or equal to 5 mu m), so that the state of the drug liquid can be effectively improved, and the tablet weight difference is ensured to meet the regulations. The phloroglucinol described below is phloroglucinol dihydrate in which the starting phloroglucinol in formulas 1-6 has not been subjected to the micronization process described herein.

Table 2 prescriptions 1-4

Table 3 prescriptions 5-7

Table 4 prescriptions 8-11

Conclusion: through tens of groups of experiments, the processing mode of the bulk drug and the composition of auxiliary materials are respectively examined by taking key quality attributes (liquid medicine state, tablet, disintegration and taste) of the freeze-dried orally disintegrating tablet as examination indexes. The selection of the disintegrating agent in the prescription is found to be important to the influence of the product, so the disintegrating agent used in the preparation of orally disintegrating tablet products by the freeze-drying method is systematically screened, and in the screening process, the inventor finds that samples obtained by the preparation process of mixing and preprocessing phloroglucinol and hydroxypropyl-beta-cyclodextrin and then mixing with pullulan, mannitol and dextran-70 are better in all indexes.

Example 3

Based on prescription 11, the amount of mannitol was slightly increased (e.g., by 2 mg) and the amount of the liquid formulation was increased to 0.45 ml/tablet. The preparation was amplified to prepare an orally-lyophilized phloroglucinol tablet (lyophilized) of lot number 191125, and the dissolution profile, content, average tablet weight, etc. were measured, wherein the average tablet weight is shown in table 5, the content measurement result is shown in table 6, and the dissolution rate of the orally-lyophilized phloroglucinol tablet (reference preparation spafen) of lot number N2080, which was ground to date, is shown in table 7, and fig. 1.

TABLE 5 average tablet weight of phloroglucinol orally disintegrating tablets (lyophilized) of lot 191125

TABLE 6 determination of the content of phloroglucinol orotic tablets (lyophilized) of lot 191125

Table 7 comparison of dissolution of the phloroglucinol orotic tablet of lot 191125 with the as-ground lyophilized tablet

The experiment proves that the phloroglucinol orally disintegrating tablet (freeze-dried) uses HP-beta-CD as a disintegrating agent, the content of the disintegrating agent is lower than 15 percent according to the total weight of the tablet, the content of the phloroglucinol is higher than 70 percent, the liquid medicine state is good, the appearance and the disintegrating effect of the prepared sample reach the expectations, and the tablet weight difference, the content and the similar factors of the dissolution curve in the water medium meet the regulations.

It will be readily appreciated by those skilled in the art that the foregoing is merely illustrative of the present invention and is not intended to limit the invention, but any modifications, equivalents, improvements or the like which fall within the spirit and principles of the present invention are intended to be included within the scope of the present invention.

Claims

1. The phloroglucinol freeze-dried orally disintegrating tablet is characterized by comprising phloroglucinol, a freeze-drying protective agent, a disintegrating agent and other medicinal excipients, wherein the freeze-drying protective agent is dextran-70, the disintegrating agent is hydroxypropyl-beta-cyclodextrin, the content of the disintegrating agent is lower than 15% based on the total weight of the tablet, the other medicinal excipients are a skeleton support agent, a binder and a sweetener, the skeleton support agent is mannitol, the binder is pullulan, the content of the phloroglucinol is higher than 70%, and the grain size D90 of the phloroglucinol is less than or equal to 5 mu m.

2. The phloroglucinol freeze-dried orally disintegrating tablet of claim 1, wherein the phloroglucinol is phloroglucinol dihydrate.

3. The phloroglucinol freeze-dried orally disintegrating tablet of claim 1, wherein the sweetener is sodium cyclamate, acesulfame potassium, sucralose, aspartame, sucrose, sodium saccharin, aspartame, dextrose, steviosin, stevioside, glycyrrhizin, thaumatin, citric acid, tartaric acid, malic acid, lactic acid, peppermint flavor, orange flavor, pineapple flavor, strawberry flavor, lemon flavor, juicy peach flavor, vanilla flavor, cherry flavor, grape flavor, chocolate flavor, or mixtures thereof.

4. The phloroglucinol freeze-dried orally disintegrating tablet of claim 1, wherein the sweetener is sucralose.

5. The phloroglucinol freeze-dried orally disintegrating tablet of claim 1, wherein the phloroglucinol freeze-dried orally disintegrating tablet comprises phloroglucinol dihydrate, mannitol, pullulan, dextran-70, sucralose, and hydroxypropyl-beta-cyclodextrin.

6. The phloroglucinol freeze-dried orally disintegrating tablet of claim 5, wherein the content of the disintegrant is less than 14%, the content of the phloroglucinol dihydrate is higher than 74%, the content of the pullulan is 0.1-0.8%, the content of the dextran-70 is 2-5%, the content of the sucralose is 0.1-1.0%, and the content of the mannitol is 7-12% based on the total weight of the tablet.

7. The phloroglucinol freeze-dried orally disintegrating tablet of claim 1, wherein each orally disintegrating tablet consists of:

8. a process for the preparation of a phloroglucinol freeze-dried orally disintegrating tablet according to any of claims 1-7, characterized in that the process comprises the steps of:

(4) And (3) freeze drying: freeze-drying for 1-12 h at-35 ℃ to 15 ℃ under the pressure of 10-500 mu bar to obtain the phloroglucinol freeze-dried orally disintegrating tablet, wherein the micro powder treatment is to treat the phloroglucinol micro powder until the particle size D90 is less than or equal to 5 mu m.