CN114099443A

CN114099443A - Oseltamivir pharmaceutical composition and preparation method and application thereof

Info

Publication number: CN114099443A
Application number: CN202010892737.4A
Authority: CN
Inventors: 李英辉; 其他发明人请求不公开姓名
Original assignee: Beijing Pangu Yinghui Technology Co ltd
Current assignee: Beijing Pangu Yinghui Technology Co ltd
Priority date: 2020-08-31
Filing date: 2020-08-31
Publication date: 2022-03-01

Abstract

An oseltamivir pharmaceutical composition, a preparation method and application thereof. The oseltamivir pharmaceutical composition comprises oseltamivir or pharmaceutically acceptable salts thereof, a beta-cyclodextrin compound and optionally other pharmaceutically acceptable auxiliary materials; wherein the mol ratio of the beta-cyclodextrin compound to the oseltamivir or the pharmaceutically acceptable salt thereof is as follows: 7-50: 1. The pharmaceutical composition can completely cover the extremely bitter taste of the oseltamivir or the pharmaceutically acceptable salt thereof by adopting the beta-cyclodextrin compound and the oseltamivir or the pharmaceutically acceptable salt thereof in a proper proportion, does not influence the dissolution and bioavailability of the medicine, has smooth and slightly sweet mouthfeel after being dissolved in water, and is particularly suitable for the old, children and other patients with severe dysphagia.

Description

Oseltamivir pharmaceutical composition and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to an oseltamivir medicinal composition, and a preparation method and application thereof.

Background

Oseltamivir (Oseltamivir), its chemical name is: (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester. The structural formula is as follows:

is an antiviral drug, and has the function of inhibiting viral neuraminidase so as to prevent the spread and release of viruses in host cells.

Oseltamivir phosphate is a drug approved by the world health organization for clinical treatment of influenza

The active ingredient of (1).

Internationally recognized

Can be used for resisting avian influenza virus and influenza A virus H1N 1. The FDA approved oseltamivir phosphate for anti-influenza use in infants and children over two weeks of age in 2012. Because the continuous variability of influenza virus genotypes and the sudden nature of outbreaks seriously affect our lives, oseltamivir phosphate has been used as a national stock drug.

Currently commercially available from Roche

For oral capsules, unit doses are 30, 45 and 75 mg.

To swallow these capsules, the treatment requires that the patient swallow them in a timely and rational manner. However, for some special patients, such as elderly people with influenza or infants, swallowing solid preparations is itself difficult.

In the above case, it is recommended to use a simpler and more acceptable liquid formulation. Of Roche

The capsule can be opened and mixed with sweet liquid such as common syrup or chocolate syrup, corn syrup, and light brown sugar water for administration.

Another product is oseltamivir phosphate dry-mixed suspension powder of the company, which contains 360mg of oseltamivir phosphate, and is suspended in water to be taken according to the age of body weight (the actual active ingredient dosage is 6 mg/ml).

The problems that follow are inaccuracy in dosage according to age and weight of infants and children, and an extremely bitter taste that oseltamivir phosphate is difficult to tolerate after rapidly dissolving in water. The relationship between the administration dose and the body weight and the age of the two dosage forms of the oseltamivir phosphate suspension and the capsule updated in 8 months in 2019 by FDA is shown in the following table 1:

TABLE 1

Patent document CN1820744A provides a preparation method of oseltamivir phosphate and its granules. Wherein each gram of the granules contains 0.0197 to 0.198g of oseltamivir phosphate, and other components comprise diluent, adhesive and optional edible essence, sweetener and/or edible pigment, and the granules with different specifications can be selected according to the age and the weight of patients. In particular, the first example provides oseltamivir phosphate granules, wherein the active ingredient accounts for 2.5 wt%, the sweetening agent sucrose accounts for as high as 94.7%, and the qualitative and quantitative compositions are shown in table 2:

TABLE 2

Sucrose is one of the most common factors that contribute to the incidence of dental caries. Although sucrose is a natural sweetener, adverse effects can occur when a large proportion of the sucrose in the granules is metabolized by oral bacteria (especially streptococcus mutans) to weak organic acids. These acids lower the oral pH below a critical value (5.5), leading to demineralization of the enamel and progression of the disease to caries. Moreover, the preparation can not completely cover the extremely bitter taste of the main drug when the main drug is taken orally, but has taste experience of extremely sweet and extremely bitter, which is more difficult for patients to accept.

Patent document CN103315965A relates to an oral solid granule suitable for infants and children and a preparation method thereof. Wherein the pellet is a composition with a particle size of 0.1-0.50mm and composed of a drug-loaded pellet core and a coating layer. The drug in the drug-carrying pellet core is oseltamivir or pharmaceutically acceptable salt, which accounts for 10-40% of the pellet proportion, and the material used in the coating layer is acrylic resin IV, which accounts for 1-50% of the pellet total weight.

For children or elderly patients, when the pellet preparation is taken with syrup, part of the active ingredients of the medicine still directly contact with tongue taste buds of the patients and other taste receptors in the oral cavity, which undoubtedly increases the discomfort of the patients. Also, the formulation affects the in vivo release of the drug as well as the bioavailability of the drug. In addition, the pellet coating preparation process is complex, time-consuming and labor-consuming. Moreover, because of the property of the polyacrylic resin IV as a coating material, the coating solution contains more than 95% of organic solvent, which increases the preparation cost of the pellet and causes environmental pollution.

The cyclodextrin inclusion technique can change the solubility of the drug, promote drug absorption, improve bioavailability, improve drug stability, reduce drug irritation, relieve adverse side effects, and mask unpleasant odor and taste of the drug.

Patent document WO2010143207 discloses an oral taste-masking pharmaceutical composition of an anti-influenza virus drug, wherein in example 2, it is disclosed that beta-cyclodextrin and oseltamivir phosphate are ground according to a dosage ratio of 1: 1, and then are prepared into dispersible tablets together with other auxiliary materials, and the conclusion that the dispersible tablets have excellent taste is given, but specific data of the excellent taste is not given, a specific method for evaluating the taste is not given, and a standard and basis for evaluating the taste are not given.

Journal articles (J.pharm.Sci. & Res.2010, 2 (9): 583-589) disclose an inclusion compound of beta-cyclodextrin and oseltamivir phosphate in a molar ratio of 1: 1 for masking bitter taste. Each volunteer judged the taste of the sample using a 5-point score ranging from 0 to 4(0 being pleasant, 1 being tasteless, 2 being slightly bitter, 3 being moderately bitter, 4 being extremely bitter). As a result, the pure oseltamivir phosphate bulk drug scored 4, indicating an extremely bitter taste; while the inclusion score was 2, indicating a slightly bitter taste. It can be seen that the inclusion compound of beta-cyclodextrin and oseltamivir phosphate according to the dosage ratio of 1: 1 does not achieve the complete taste masking effect.

Patent document CN102526014A discloses a pharmaceutical composition comprising oseltamivir phosphate and at least one beta-cyclodextrin or a derivative thereof, which may be capable of reducing the side effects of nausea and vomiting. In the pharmaceutical composition in the examples of the patent document, oseltamivir phosphate and β -cyclodextrin or a derivative thereof form an inclusion compound, and the inclusion rate is 95 or more. The test results provided in this patent document show that the 3 test groups (oseltamivir phosphate compositions of examples 1, 2, 3) had less emetic side effects than the control group C (physical mixture of methyl β -cyclodextrin and oseltamivir phosphate 10: 1). Also, the vomiting side effect was not further reduced or increased slightly for the compositions of examples 3 and 8 having a relatively high cyclodextrin content (10: 1 and 5: 1 weight ratio of cyclodextrin to oseltamivir phosphate, respectively) compared to the composition of example 2 having a relatively low cyclodextrin content (1: 10 weight ratio of cyclodextrin to oseltamivir phosphate). Tests have shown that the various physical mixtures and inclusion compounds disclosed in the above-mentioned patent document CN102526014A do not completely mask the extremely bitter taste of oseltamivir phosphate.

Disclosure of Invention

For patients, especially infants and the elderly, oseltamivir or the pharmaceutically acceptable salt thereof should be easy to swallow when taken, and have no unacceptable taste during oral administration, so that the patients do not generate a psychological conflict. It is therefore desirable to provide a pharmaceutical particle size that minimizes the size of oseltamivir or a pharmaceutically acceptable salt thereof while completely masking the unpleasant taste of the drug.

In terms of preparation process, the production cost of the oseltamivir or the pharmaceutically acceptable salt thereof is reduced to the greatest extent, and the preparation process is environment-friendly, simple and feasible.

For pharmaceutical workers, appropriate prescriptions and dosage forms must be designed by means of preparations, so that the purposes are achieved, the dissolution and absorption of the medicine are ensured to meet the treatment effect, and the stability is good.

In order to solve the technical problems, the inventor strives to develop the simplest formulation and manufacturing process, overcomes the defects of the existing oseltamivir phosphate medicinal preparation, provides a medicinal composition of oseltamivir or a pharmaceutically acceptable salt thereof, which can be used by a patient at ease, is easy to swallow when being taken, has good stability, high dissolution speed and good release effect, can completely cover the extremely bitter taste of the oseltamivir or the pharmaceutically acceptable salt thereof, and improves the compliance and the convenience of medicament treatment.

Cyclodextrin mainly plays roles of changing the solubility of a medicament, promoting medicament absorption, improving bioavailability, improving medicament stability, reducing medicament irritation, relieving toxic and side effects, covering unpleasant odor and taste of the medicament and the like by forming an inclusion compound with the medicament. In the case where the inclusion compound is sufficiently formed, the above-mentioned technical effect is not necessarily further improved by further increasing the amount of cyclodextrin, and as disclosed in the above-mentioned patent document CN102526014A, in which the inclusion rate of oseltamivir phosphate is 95% or more by using an excessive amount of cyclodextrin in the composition, the emesis-reducing effect cannot be further improved by further increasing the amount of cyclodextrin, and the bitter taste of oseltamivir phosphate cannot be completely masked by each composition in the document.

The present inventors have unexpectedly found that a composition comprising a cyclodextrin compound and oseltamivir or a pharmaceutically acceptable salt thereof in a sufficiently high molar ratio can completely inhibit the extremely bitter taste of the drug and increase compliance of children, the elderly and patients suffering from dysphagia.

In view of this, the present invention provides a pharmaceutical composition comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a cyclodextrin compound and optionally other pharmaceutically acceptable auxiliary materials; the preparation method is characterized in that the molar ratio of the cyclodextrin compound to the oseltamivir or the pharmaceutically acceptable salt thereof is as follows: 7-50: 1; preferably 10-30: 1, more preferably 12-20: 1, more preferably 15-18: 1, more preferably 15: 1 or 18: 1.

The molar ratio of the above cyclodextrin compound and oseltamivir or a pharmaceutically acceptable salt thereof may be converted to a mass ratio. The mass ratio of the cyclodextrin compound to oseltamivir or a pharmaceutically acceptable salt thereof in the composition of the present invention may be, for example, 17-150: 1, depending on the molecular weight of the cyclodextrin compound and oseltamivir or a pharmaceutically acceptable salt thereof; preferably, it may be 20 to 144: 1, more preferably 25 to 90: 1, still more preferably 30 to 60: 1; further preferably 40-50: 1.

In one example, the mass ratio of hydroxypropyl-beta-cyclodextrin to oseltamivir phosphate is 41.5: 1 or 50: 1.

In one example, the mass ratio of dimethyl-beta-cyclodextrin to oseltamivir phosphate is 47.7: 1.

In one example, the mass ratio of sulfobutyl- β -cyclodextrin to oseltamivir phosphate is 1: 66.67, alternatively 43.4: 1.

Preferably, the oseltamivir pharmaceutically acceptable salt comprises a salt of oseltamivir with an inorganic salt selected from nitric acid, hydrochloric acid, sulfuric acid, perchloric acid and phosphoric acid; or, a salt of oseltamivir added with an organic acid selected from the group consisting of acetic acid, propionic acid, glycolic acid, lactic acid, propionic acid, citric acid, tartaric acid, and salicylic acid; preferably, the oseltamivir pharmaceutically acceptable salt is oseltamivir phosphate.

Preferably, the cyclodextrin-based compound is selected from one or more of β -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin (preferably dimethyl- β -cyclodextrin), glucosyl- β -cyclodextrin (e.g., monoglucosyl- β -cyclodextrin or diglucosyl- β -cyclodextrin), sulfobutyl- β -cyclodextrin, and maltosyl- β -cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin.

Preferably, the oseltamivir or the pharmaceutically acceptable salt thereof is oseltamivir phosphate, and the cyclodextrin compound is hydroxypropyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin.

Preferably, the other pharmaceutically acceptable excipients include one or more of sweeteners, flavoring agents and bitterness inhibitors; preferably comprising an orange bitter taste inhibitor and/or stevia anhydride.

Preferably, the mass ratio of the total amount of the sweetening agent, the flavoring agent and/or the bitter taste inhibitor to the oseltamivir or the pharmaceutically acceptable salt thereof is (0-1): 1, preferably 0.005-0.5: 1, more preferably 0.01-0.2: 1, and more preferably 0.08-0.16: 1.

Preferably, the dosage form of the pharmaceutical composition is granules. The granules described in the present invention may also be referred to as dry powders.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: screening the oseltamivir or the pharmaceutically acceptable salt thereof, the beta-cyclodextrin compound and optional pharmaceutically acceptable auxiliary materials, and then physically mixing.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: adding the beta-cyclodextrin compound into water for dissolving, adding oseltamivir or pharmaceutically acceptable salt thereof, dissolving, and drying (preferably freeze-drying).

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

(1) respectively sieving oseltamivir or pharmaceutically acceptable salts thereof, a beta-cyclodextrin compound and optional pharmaceutically acceptable auxiliary materials, and physically and uniformly mixing;

(2) adding wetting agent to prepare soft material, and performing wet granulation to obtain wet granules; optionally, the wetting agent is selected from water or 80-20% ethanol, preferably 80% ethanol is the wetting agent;

(3) drying the wet granules.

Preferably, the pharmaceutical composition can be prepared by the following method:

(1) oseltamivir or a pharmaceutically acceptable salt thereof, a beta-cyclodextrin compound and optionally other pharmaceutically acceptable auxiliary materials; sieving with 80-120 mesh sieve (preferably 100 mesh sieve), precisely weighing the sieved powder, and physically mixing;

(2) adding wetting agent, making into soft material, sieving with 12-16 mesh sieve (preferably 14 mesh sieve for granulating), and drying the wet granules at 40-50 deg.C (preferably 45 deg.C); optionally, the wetting agent is water or 80-20% ethanol, preferably 80% ethanol is the wetting agent;

sieving the obtained dry granules with 12-16 mesh sieve (preferably 14 mesh sieve), drying, grading, sieving with 60-100 mesh sieve (preferably 80 mesh sieve), and removing fine powder.

In the pharmaceutical composition of the invention, the cyclodextrin compound and the oseltamivir or the pharmaceutically acceptable salt thereof can be physical mixtures, or the inclusion compound and the physical mixtures coexist.

In one embodiment, the excess cyclodextrin compound is in powder form in a physical mixture with oseltamivir or a pharmaceutically acceptable salt thereof. When the composition is used by a patient, water is added and mixed to quickly form an inclusion compound of oseltamivir or a pharmaceutically acceptable salt thereof and a cyclodextrin compound.

In one embodiment, the pharmaceutical composition of the present invention may also be prepared in a clathrate-containing form. The preparation method is well known to those skilled in the pharmaceutical field, such as ultrasonic method, grinding method, stirring method, and freeze-drying method.

In one example, a predetermined amount of beta-cyclodextrin compound is dissolved in a proper amount of water, stirred to be completely dissolved, a predetermined amount of oseltamivir or a pharmaceutically acceptable salt thereof is added, stirred, mixed uniformly and then freeze-dried, and the freeze-dried powder is subpackaged into aluminum foil bags, glass bottles or plastic bottles, preferably aluminum foil bags. The ratio of β -cyclodextrin compound to water is readily determined by one skilled in the art.

The invention also provides application of the pharmaceutical composition in preparing anti-influenza virus drugs. Examples of the influenza virus include avian influenza virus and influenza a H1N1 virus.

The pharmaceutical composition can be prepared by water or other media before use, and can be quickly dissolved to form a clear and transparent solution, so that the pharmaceutical composition can be used by patients and has good solution stability. Is especially suitable for infants, children, the old and other patients who have difficulty in swallowing solid preparations, and the dosage of the medicine can be selected according to different specifications of the body weight of the patients. Convenient transportation and is friendly to patients. The solution system is uniform and convenient for dividing the dosage, the preparation process is simple and easy to implement, and the production cost is reduced.

The preparation of a pharmaceutical solution for extemporaneous preparation from a pharmaceutical composition of the invention may be prepared, for example, by the following method: adding water into the aluminum foil bag, mixing completely, dissolving completely, masking taste, and making clear and transparent solution for administration according to body weight and age.

Has the advantages that:

the preparation form of the pharmaceutical composition has the characteristics of simple formula and process, direct oral administration after rapid dissolution in water, and is superior to the prior oral solid preparations and liquid preparations such as suspension and the like. The solution is clear and transparent after being dissolved in water, can well cover the bad taste of oseltamivir, has smooth and slightly sweet taste, does not influence the dissolution of the medicine, has good stability, high dissolution speed and good release effect, and is particularly suitable for infants, children, old people and other patients who have difficulty in swallowing solid preparations.

The medicinal composition can realize personalized medication according to age and weight. Compared with the capsule sold in the market, the capsule is more convenient to swallow; compared with the suspension, the liquid has smaller volume, smoother taste and accurate dosage of the active ingredients; compared with the existing granule, the preparation method is simpler and more environment-friendly.

Description of the drawings:

FIG. 1: a schematic diagram of oseltamivir phosphate drug granules prepared in example 3;

FIG. 2: drug release profiles in water of the taste-masked particles of examples 1 and 3;

FIG. 3: a taste masking effect evaluation chart of oseltamivir phosphate pharmaceutical compositions obtained in example 1 and comparative example 1;

FIG. 4: example 3 and commercial pediatric formula taste masking effect evaluation graph.

Detailed Description

The present invention will be further described below with reference to specific embodiments. It should be noted that the following detailed description is merely exemplary in nature and is not intended to limit the scope of the invention.

In the following examples, the information on the production of each adjuvant is as follows:

example 1: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Hydroxypropyl-beta-cyclodextrin	15	13.53g

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the oseltamivir phosphate and the hydroxypropyl-beta-cyclodextrin according to the prescription amount, and physically and uniformly mixing; subpackaging into aluminum foil bags, each bag containing 30mg of oseltamivir phosphate.

Example 2: preparation of oseltamivir phosphate pharmaceutical composition

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the hydroxypropyl-beta-cyclodextrin in the amount of the formula, adding the obtained mixture into a beaker containing water, stirring at room temperature until the mixture is completely dissolved, adding oseltamivir phosphate into the system, stirring until the mixture is completely dissolved, carrying out freeze-drying treatment for 24 hours, and subpackaging the obtained product in aluminum foil bags, wherein each bag contains 45mg of oseltamivir phosphate.

Example 3: preparation of oseltamivir phosphate pharmaceutical composition

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the oseltamivir phosphate and the hydroxypropyl-beta-cyclodextrin according to the prescription amount, and physically and uniformly mixing; adding a little 80% ethanol, making into soft material, sieving with 14 mesh sieve, granulating, drying wet granules at 45 deg.C, sieving with 14 mesh sieve, grading, sieving with 80 mesh sieve, and removing fine powder to obtain oseltamivir phosphate granules. The preparation flow diagram is shown in figure 1.

Example 4: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Hydroxypropyl-beta-cyclodextrin	18	16.24g

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the oseltamivir phosphate and the hydroxypropyl-beta-cyclodextrin in the prescribed amount, sieving the powders, and physically and uniformly mixing the powders; subpackaging into aluminum foil bags, each bag containing 30mg of oseltamivir phosphate.

Example 5: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Dimethyl-beta-cyclodextrin	15	11.68g
			Stevia anhydride		0.04g

Respectively sieving oseltamivir phosphate, dimethyl-beta-cyclodextrin and stevia anhydride with a 100-mesh sieve, precisely weighing the oseltamivir phosphate, the dimethyl-beta-cyclodextrin and the stevia anhydride with the above prescription amount, and physically and uniformly mixing; subpackaging into aluminum foil bags, each bag containing 30mg of oseltamivir phosphate.

Example 6: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Sulfobutyl-beta-cyclodextrin	15	12.74g
			Orange-flavored bitterness inhibitor		0.02g

Respectively sieving oseltamivir phosphate, sulfobutyl-beta-cyclodextrin and an orange bitter taste inhibitor by a 100-mesh sieve, precisely weighing the oseltamivir phosphate, the sulfobutyl-beta-cyclodextrin and the orange bitter taste inhibitor according to the prescription amount, and physically and uniformly mixing; subpackaging into plastic bottles, each bottle containing 30mg of oseltamivir phosphate.

Comparative example 1: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Hydroxypropyl-beta-cyclodextrin	3.6	3.25g

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the oseltamivir phosphate and the hydroxypropyl-beta-cyclodextrin according to the prescription amount, and physically and uniformly mixing; subpackaging into tinfoil bags, each bag containing 30mg of oseltamivir phosphate.

Comparative example 2: preparation of oseltamivir phosphate pharmaceutical composition

Components	Molar ratio of	Weight (D)
			Oseltamivir phosphate	1	0.24g
Hydroxypropyl-beta-cyclodextrin	1	0.90g

Respectively sieving oseltamivir phosphate and hydroxypropyl-beta-cyclodextrin by a 100-mesh sieve, precisely weighing the oseltamivir phosphate and the hydroxypropyl-beta-cyclodextrin according to the prescription amount, and physically and uniformly mixing; subpackaging into plastic bottles, wherein each bottle contains 30mg of oseltamivir phosphate.

Preparation example 1:

the oseltamivir phosphate pharmaceutical compositions obtained in the examples 1-6 and the comparative examples 1-2 are respectively prepared into 3mg/ml anti-influenza virus taste masking solution according to the mass of the oseltamivir phosphate and the mass of water in the prescription.

Test example 1: taste masking effect evaluation test of oseltamivir phosphate pharmaceutical composition

6 adult male and female of 20-45 years old were selected as evaluators, and the oseltamivir phosphate pharmaceutical composition was orally administered. The bitterness level was measured immediately after the drug was taken (0 second) and 30 seconds after the drug was completely dissolved. The criteria for assessing bitterness are shown below, the total scores are averaged together and reported in table 1, with higher scores indicating more bitterness.

Criteria for evaluating bitterness:

0: slightly sweet and acceptable

1: has no bitter taste

2: minimal bitter taste

3: slight bitter taste

4: is bitter

5: has strong bitter taste

6: intolerable bitter taste

TABLE 1 taste masking Effect evaluation results of oseltamivir phosphate pharmaceutical compositions of the different examples and comparative examples

The taste masking effect evaluation test results in table 1 show that the oseltamivir phosphate pharmaceutical composition of the present invention has good taste effect and is easy to accept, which will undoubtedly increase patient compliance and achieve the purpose of taste masking.

Test example 2: evaluation of Release Effect of different taste-masking particles

The release effect of the pharmaceutical compositions of examples 1 and 3 was determined by dissolution method (second method of general rule 0931) using water as dissolution medium at 900ml and 50r/min for 5min, 10min, 20min, 30min and 45 min. After sampling, the drug dissolution was measured by HPLC and the dissolution profile was plotted. The test results are shown in table 2 and fig. 2.

The dissolution results were measured by the following measurement methods. A chromatographic column: c⁸Column (Sunfire)^TM C⁸5.0 μm, 4.6 × 250 Column); mobile phase: potassium dihydrogen phosphate solution [ 0.05mol/L, pH adjusted to 6.0 with 1mol/L potassium hydroxide solution ] -methanol-acetonitrile (62: 24.5: 13.5, V/V/V); detection wavelength: 207 nm; flow rate: 1.2 ml/min; column temperature: 35 ℃; sample introduction amount: 15 mu l of the solution; methanol-acetonitrile-water (24.5: 13.5: 62, V/V/V) is used as a diluent for dissolving drugs or diluting sample solutions.

TABLE 2

Sample (I)	Dissolution rate of 5min	30min dissolution (%)
			Example 1	98％	99％
Example 3	97％	98％

The experimental result of drug release effect evaluation shows that the oseltamivir phosphate pharmaceutical composition can be rapidly dissolved in water, and the preparation process does not influence the drug release of the drug in the gastrointestinal tract.

The following test examples 3 and 4 were each evaluated for taste masking effect of oseltamivir phosphate pharmaceutical compositions by the following measurement method:

the oseltamivir phosphate pharmaceutical composition is added into 25ml deionized water, and after dissolution, a filtered sample is collected into an E-Tongue (alpha MOS) sample holder through a 0.45um nylon filter. The test was repeated 8 times for each sample, and the signal was collected for 120 seconds each time. After collecting the signal from each sample, the sensor was rinsed in water for 120 seconds. An acquisition database of between 100 seconds and 120 seconds is established. Seven repeated sensor (AHS, PKS, CTS, NMS, CPS, ANS, SCS) signals were used for principal component analysis. Using principal component analysis, data points can be compared by measuring the distance between one or a group of samples. The distance is an euclidean example between the cluster computation center of one sample set to the cluster computation center of another sample set. A Discrimination Index (DI) from negative to 100 is reported on the principal component analysis map, with higher scores indicating better discrimination (or less similarity) between samples or groups.

Measurement and sensor data processing: AlphaSoft software (V15.0).

Test example 3

Hydroxypropyl-beta-cyclodextrin, oseltamivir phosphate as a main drug and the oseltamivir phosphate pharmaceutical compositions of the example 1 and the comparative example 1 containing the same mass of oseltamivir phosphate are respectively weighed, 25ml of deionized water is added to prepare a solution of 3mg/ml, after dissolution, a filtered sample is filtered by a 0.45um nylon filter, and the taste masking effect of the filtered sample is evaluated by E-tongue (alpha MOS).

The taste-masking evaluation test results are shown in fig. 3, and the results show that the oseltamivir phosphate pharmaceutical composition in the comparative example 1 has little taste difference with the main drug, and cannot mask the extremely bitter taste of the main drug, while the oseltamivir phosphate pharmaceutical composition in the example 1 has obvious taste difference with the main drug, can completely mask the bitter taste of the drug, and is consistent with the taste results of the experimental example 1.

Test example 4

Hydroxypropyl-beta-cyclodextrin, oseltamivir phosphate as a main drug, the oseltamivir phosphate pharmaceutical composition of example 3 and a commercially available children preparation (15mg/ml, in Yichangdong sunshine Yangtze river pharmaceutical industry) containing the same mass of oseltamivir phosphate were added with 25ml of deionized water to prepare a 3mg/ml solution, and after dissolution, the filtered sample was evaluated for taste masking effect with an E-tongue (alpha MOS) filter with a 0.45um nylon filter.

The taste masking evaluation experiment result is shown in fig. 4, and the result shows that the difference between the commercially available children preparation and the main drug is small, namely the difference between the extremely bitter taste channels of the commercially available children preparation and the main drug is not large. The taste difference between the oseltamivir phosphate medicine composition and the main medicine in the embodiment 3 is large, so that the bitter taste of the main medicine can be completely covered, and the result is consistent with the result obtained by a mouth taste method.

Claims

1. A pharmaceutical composition comprising: oseltamivir or a pharmaceutically acceptable salt thereof, a cyclodextrin compound and optionally other pharmaceutically acceptable auxiliary materials; the preparation method is characterized in that the molar ratio of the cyclodextrin compound to the oseltamivir or the pharmaceutically acceptable salt thereof is as follows: 7-50: 1; preferably 10-30: 1, more preferably 12-20: 1, more preferably 15-18: 1, more preferably 15: 1 or 18: 1.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of oseltamivir comprises a salt of oseltamivir with an inorganic salt selected from the group consisting of nitric acid, hydrochloric acid, sulfuric acid, perchloric acid, and phosphoric acid; or, a salt of oseltamivir added with an organic acid selected from the group consisting of acetic acid, propionic acid, glycolic acid, lactic acid, propionic acid, citric acid, tartaric acid, and salicylic acid; preferably, the oseltamivir pharmaceutically acceptable salt is oseltamivir phosphate.

3. The pharmaceutical composition according to claim 1 or 2, wherein the cyclodextrin compound is selected from one or more of β -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin (preferably dimethyl- β -cyclodextrin), glucosyl- β -cyclodextrin (e.g. mono-or di-glucosyl- β -cyclodextrin), sulfobutyl- β -cyclodextrin and maltosyl- β -cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin;

4. The pharmaceutical composition of any one of claims 1-3, wherein the other pharmaceutically acceptable excipients comprise one or more of sweeteners, flavoring agents, and bitter taste suppressors; preferably comprising an orange bitter taste inhibitor and/or stevia anhydride.

5. The pharmaceutical composition according to claim 4, wherein the mass ratio of the total amount of the sweetener, the flavoring agent and/or the bitter taste inhibitor to the oseltamivir or the pharmaceutically acceptable salt thereof is (0-1): 1, preferably 0.005-0.5: 1, more preferably 0.01-0.2: 1, more preferably 0.08-0.16: 1.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is in the form of granules.

7. A process for preparing a pharmaceutical composition according to any one of claims 1 to 6, comprising: screening the oseltamivir or the pharmaceutically acceptable salt thereof, the beta-cyclodextrin compound and the optional pharmaceutically acceptable auxiliary materials, and then physically mixing.

8. A process for preparing a pharmaceutical composition according to any one of claims 1 to 6, comprising: dissolving beta-cyclodextrin compound in water, adding oseltamivir or pharmaceutically acceptable salt thereof and optional pharmaceutically acceptable adjuvants such as sweetener, etc., dissolving, and drying (preferably lyophilizing).

9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 6, comprising:

(3) drying the wet granules.

10. Use of a pharmaceutical composition as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of influenza virus.