Olopatadine oral rapidly disintegrating tablet composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an olopatadine oral rapidly disintegrating tablet composition and a preparation method thereof, the composition is composed of olopatadine, mannitol, a taste masking agent, a disintegrating agent, a flavoring agent, colloidal silica and magnesium stearate; the olopatadine tablet comprises the following components in percentage by weight: 1.0 to 10.0 percent of olopatadine, 30.0 to 90.0 percent of mannitol, 0.01 to 1.0 percent of taste masking agent, 0.01 to 1.0 percent of flavoring agent, 1.0 to 10.0 percent of disintegrating agent, 0.5 to 5.0 percent of colloidal silicon dioxide and 0.5 to 15.0 percent of magnesium stearate. The composition prepared by adopting the prescription can improve the stability of the medicine, the in-vitro dissolution curve is consistent with that of a reference preparation, the taste is good, and the smoothness of a patient can be improved in the taking process.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to an olopatadine orally rapidly disintegrating tablet composition and a preparation method thereof. Background Art

[0002] Allergic rhinitis and conjunctivitis are the most common allergic diseases, affecting 30% of adults and 40% of children. Allergic rhinitis and allergic conjunctivitis have similar pathophysiological mechanisms, mainly including type I IgE-mediated inflammatory response. Allergic rhinitis is characterized by nasal itching, nasal congestion, sneezing and rhinorrhea; the main symptoms of allergic conjunctivitis are erythema, tearing, eyelid swelling, itching of both eyes, etc., which have a serious impact on people's daily life.

[0003] Olopatadine hydrochloride is an antiallergic agent created by the former Kyowa Hakko Kogyo Co., Ltd. (now Kyowa Kirin Co., Ltd.) that is a zwitterionic compound in terms of chemical structure. It is a typical dual-action drug that antagonizes histamine and stabilizes mast cell membranes. Most of its actual applications are concentrated on the treatment of allergic conjunctivitis through the nasal cavity and intraocular route. It has been recommended as a first-line treatment drug by domestic and international guidelines.

[0004] At present, the dosage forms of olopatadine hydrochloride mainly include tablets, capsules, granules and oral solutions. These dosage forms involve the problem of rapid dissolution after taking, and the medication compliance of groups with difficulty in swallowing, such as the elderly and children, is poor. In addition, olopatadine hydrochloride is easily degraded under light and oxidative conditions. Other olopatadine hydrochloride formulations on the market also have more or less poor taste, medication compliance and drugability need to be further improved, drug dissolution performance needs to be further improved, and the single dose is large, which is not suitable for children.

[0005] In May 2010, Kyowa Kirin Co., Ltd. obtained the production license for 2.5mg and 5mg olopatadine hydrochloride orodisintegrating tablets (trade name Allelock), and in July of the same year, the applicable population, indications, and usage and dosage were added (for itching caused by allergic rhinitis, urticaria, and skin diseases (eczema, dermatitis, and pruritus) in children over 7 years old). Olopatadine hydrochloride orodisintegrating tablets are currently only available in Japan and are not available in other countries. The olopatadine hydrochloride raw material itself has a bitter taste. In order to improve its taste and stability, Allelock uses a three-step granulation method according to Japanese patent JPWO2012029348A1, which has high technical barriers and high costs. There are no orodisintegrating tablets containing olopatadine on the market in China.

[0006] It can be seen that it is imperative to develop a pediatric pharmaceutical composition containing olopatadine hydrochloride with obvious drug efficacy, good taste, good patient compliance in taking medicine, good stability, simple preparation process and low cost, and its preparation method. It has broad market value and application prospects and is of great significance for promoting the development of the olopatadine hydrochloride preparation field. Therefore, an olopatadine orally disintegrating tablet composition and its preparation method are provided. Summary of the Invention

[0007] The purpose of the present invention is to provide an olopatadine orally disintegrating tablet composition and its preparation method in view of the defects of the prior art, so as to solve the problems raised in the above background technology.

[0008] To achieve the above purpose, the present invention provides the following technical solution: An olopatadine orally disintegrating tablet composition, which is composed of olopatadine, mannitol, taste masking agent, disintegrant, flavoring agent, colloidal silicon dioxide and magnesium stearate; Calculated by weight percentage, the dosage proportion of olopatadine is 1.0 - 10.0%, the dosage proportion of mannitol is 30.0 - 90.0%, the dosage proportion of taste masking agent is 0.01 - 1.0%, the dosage proportion of flavoring agent is 0.01 - 1.0%, the dosage proportion of disintegrant is 1.0 - 10.0%, the dosage proportion of colloidal silicon dioxide is 0.5 - 5.0%, and the dosage proportion of magnesium stearate is 0.5 - 15.0%.

[0009] As a preferred technical solution of the present invention, the taste masking agent is methacrylic acid copolymer.

[0010] As a preferred technical solution of the present invention, the flavoring agent is any one or a combination of neotame, sucralose and essence.

[0011] As a preferred technical solution of the present invention, the disintegrant is any one or a combination of crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose.

[0012] As a preferred technical solution of the present invention, the mannitol is mannitol 200SD.

[0013] A preparation method of the olopatadine orally disintegrating tablet composition as described above, comprising the following steps: Step 1: Pretreat olopatadine and control the particle size, and control the particle size of olopatadine D 90 to 10 - 150 μm; Step 2: Screen and mix olopatadine and the taste masking agent; Step 3: Add the flavoring agent to the materials in Step 2 and continue to screen and mix; Step 4: Mix mannitol with colloidal silicon dioxide and the disintegrant and screen; Step 5: After mixing the mixtures from Step 3 and Step 4, add magnesium stearate and mix thoroughly, then perform tabletting.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides an olopatadine orally disintegrating tablet and a preparation method thereof. The preparation contains an active ingredient of olopatadine, mannitol, a taste masking agent, a disintegrant, a flavoring agent, colloidal silicon dioxide, and magnesium stearate. The composition prepared with this formulation can improve the stability of the drug, the in vitro dissolution curve is consistent with the reference preparation, and it has a good taste, which can increase the palatability of patients during administration.

[0015] Compared with the three-step granulation process used in the original research product Allelock, the present invention innovatively adopts a step-by-step mixing process: first premix the active pharmaceutical ingredient (API) with the taste masking agent, then mix with the flavoring agent, and finally directly tablet after uniformly mixing with other excipients; this process has the following outstanding advantages: (1) The preparation process is significantly simplified, and the production cost is greatly reduced; (2) The obtained tablets have good oral palatability, significantly improving the compliance of patients with medication; (3) The in vitro quality indicators and stability are consistent with the original research product Allelock. The present invention provides a more industrialized advantageous preparation scheme for olopatadine preparations. Description of the Drawings

[0016] Figure 1 It is the dissolution curve of the self-made product and the reference product in Example 2 of the present invention in an aqueous medium. Detailed Embodiments

[0017] The following elaborates on the preferred embodiments of the present invention in conjunction with the drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0018] The present invention provides a technical solution: an olopatadine rapidly orally disintegrating tablet composition, which is composed of olopatadine, mannitol, a taste masking agent, a disintegrant, a flavoring agent, colloidal silicon dioxide, and magnesium stearate; By weight percentage, the dosage proportion of olopatadine is 1.0 - 10.0%, the dosage proportion of mannitol is 30.0 - 90.0%, the dosage proportion of the taste masking agent is 0.01 - 1.0%, the dosage proportion of the flavoring agent is 0.01 - 1.0%, the dosage proportion of the disintegrant is 1.0 - 10.0%, the dosage proportion of colloidal silicon dioxide is 0.5 - 5.0%, and the dosage proportion of magnesium stearate is 0.5 - 15.0%.

[0019] The taste masking agent is a copolymer of methacrylic acid.

[0020] The flavoring agent is any one or a combination of neotame, sucralose, and essence.

[0021] The disintegrant is any one or a combination of multiple ones of cross-linked povidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose.

[0022] A preparation method of the olopatadine orally disintegrating tablet composition as described above comprises the following steps: Step 1: Pretreat olopatadine to control the particle size, and control the particle size of olopatadine D 90 to be 10 - 150 μm; Step 2: Sieve and mix olopatadine and the taste masking agent; Step 3: Add the flavoring agent to the materials in Step 2 and continue to sieve and mix; Step 4: Mix mannitol with colloidal silicon dioxide and the disintegrant and sieve; Step 5: After mixing the mixtures of Step 3 and Step 4, add magnesium stearate for overall mixing, and then carry out tabletting.

[0023] Example 1: The prescription composition is shown in Table 1: Table 1: Composition table of Prescription 1 - 4

[0024] Preparation method: According to the preparation process of the present invention, weigh the prescription amounts of the raw and auxiliary materials respectively, mix them evenly, and then carry out tabletting.

[0025] Verification of Example 1: Taste test: Randomly select 10 volunteers (5 males and 5 females) for blind taste evaluation of the samples. Taste the samples in sequence. After tasting, rinse the mouth with drinking water until there is no residual taste of the previous tablet in the mouth, and then carry out the test for the next tablet. Rank and score according to the taste. As shown in Table 2, the best taste is 10 points and the worst is 1 point.

[0026] Table 2: Taste test table of Prescription 1 - 4 and the reference

[0027] Conclusion: For Prescription 1 - 3, the smell, sweetness, and aftertaste are slightly worse than those of the reference preparation, and the taste of Prescription 4 is the same as that of the reference preparation. Example 2: The prescription composition is shown in Table 3:

[0028] Table 3: Composition table of Prescription 5 - 10

[0029] Preparation method: For Prescription 5 - 7, weigh the prescription amounts of the raw and auxiliary materials and carry out wet granulation. After drying, carry out granule sizing and add magnesium stearate externally for overall mixing, and then carry out tabletting; For Prescription 8 - 10, weigh the prescription amounts of the raw and auxiliary materials and mix them. After mixing evenly, add magnesium stearate externally for overall mixing, and then carry out tabletting; The summary of stability data is shown in Table 4, Table 4: Summary Table of Stability Data

[0030] Conclusion: Combining Table 4 and Figure 1 as shown, Formulations 5 - 7 adopt the wet granulation process, and the trend of impurity enhancement in the stability stage is slightly faster than that of the reference preparation. In the stability stage of Formulations 8 - 9, the trend of impurity increase is the same as that of the reference preparation, but the disintegration time limit does not meet the requirements. In the stability stage of Formulation 10, the trend of impurity increase is the same as that of the reference preparation, and the disintegration time limit meets the requirements.

[0031] The above embodiments only represent the implementation modes of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. An olopatadine orally disintegrating tablet composition, characterized in that: The composition consists of olopatadine, mannitol, taste masking agent, disintegrant, flavoring agent, colloidal silicon dioxide and magnesium stearate; By weight percentage, the dosage proportion of olopatadine is 1.0 - 10.0%, the dosage proportion of mannitol is 30.0 - 90.0%, the dosage proportion of taste masking agent is 0.01 - 1.0%, the dosage proportion of flavoring agent is 0.01 - 1.0%, the dosage proportion of disintegrant is 1.0 - 10.0%, the dosage proportion of colloidal silicon dioxide is 0.5 - 5.0%, and the dosage proportion of magnesium stearate is 0.5 - 15.0%.

2. The olopatadine orally disintegrating tablet composition according to claim 1, characterized in that: The taste masking agent is a copolymer of methacrylic acid.

3. The olopatadine orally disintegrating tablet composition according to claim 1, wherein: The flavoring agent is any one or a combination of neotame, sucralose and essence.

4. The olopatadine orally disintegrating tablet composition according to claim 1, wherein: The disintegrant is any one or a combination of crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose.

5. The olopatadine orally disintegrating tablet composition according to claim 1, characterized in that: The mannitol is mannitol 200SD.

6. A method for preparing the olopatadine orally disintegrating tablet composition according to any one of claims 1-5, characterized in that: It includes the following steps: Step 1: Pretreat olopatadine to control the particle size. Control the olopatadine D 90 to 10 - 150 μm; Step 2: Sieving and mixing olopatadine and the taste masking agent; Step 3: Adding the flavoring agent to the materials in Step 2 and continuing to sieve and mix; Step 4: Mixing and sieving mannitol with colloidal silicon dioxide and the disintegrant; Step 5: After mixing the mixtures of Step 3 and Step 4, adding magnesium stearate and performing total mixing, and then tabletting.

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