Olopatadine orally rapidly disintegrating tablet composition and preparation method thereof

Abstract

This invention relates to the field of pharmaceutical formulation technology, specifically disclosing an olopatadine orally rapidly disintegrating tablet composition and its preparation method. The composition comprises olopatadine, mannitol, a taste masking agent, a disintegrant, a flavoring agent, colloidal silica, and magnesium stearate. By weight percentage, the amounts of olopatadine, mannitol, colloidal silica, and magnesium stearate are 1.0-10.0%, mannitol, colloidal silica, and magnesium stearate, respectively. The composition prepared using this formulation improves drug stability, exhibits an in vitro dissolution profile consistent with the reference formulation, and has a pleasant taste, increasing palatability during administration.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an olopatadine orally rapidly disintegrating tablet composition and its preparation method. Background Technology

[0002] Allergic rhinitis and allergic conjunctivitis share similar pathophysiological mechanisms, primarily involving type IgE-mediated inflammatory responses. Allergic rhinitis is characterized by nasal itching, nasal congestion, sneezing, and nasal discharge; allergic conjunctivitis is mainly characterized by erythema, tearing, eyelid swelling, and itching in both eyes, both of which severely impact people's daily lives.

[0003] Olopatadine hydrochloride is an anti-allergy agent with an amphoteric chemical structure, created by Kyowa Hakko Co., Ltd. (now Kyowa Kirin Co., Ltd.). It is a typical dual-action drug that antagonizes histamine and stabilizes mast cell membranes. In practice, most of its applications are focused on treating allergic conjunctivitis through nasal and intraocular routes. It has been recommended as a first-line treatment by domestic and international guidelines and consensus.

[0004] Currently, olopatadine hydrochloride is mainly available in tablet, capsule, granule, and oral solution formulations. These formulations present challenges due to rapid dissolution after administration, leading to poor medication adherence among the elderly, children, and other groups with swallowing difficulties. Furthermore, olopatadine hydrochloride is prone to degradation under light and oxidative conditions. Other commercially available olopatadine hydrochloride formulations also suffer from varying degrees of unpleasant taste, require further improvement in medication adherence and drug compatibility, have poor dissolution performance, and involve large single-dose doses, making them unsuitable for children.

[0005] In May 2010, Kyowa Kirin Co., Ltd. obtained a production license for olopatadine hydrochloride orally disintegrating tablets 2.5mg and 5mg (trade name Allelock). In July of the same year, the applicable population, indications, and dosage were added (for itching caused by allergic rhinitis, urticaria, and skin diseases (eczema, dermatitis, pruritus) in children over 7 years of age). Olopatadine hydrochloride raw material itself has a bitter taste. To improve its taste and stability, Allelock uses a three-step granulation method according to Japanese patent JPWO2012029348A1. This method has high technical barriers and high costs, and there are currently no orally disintegrating tablets containing olopatadine on the market in China.

[0006] It is evident that developing a pediatric drug composition containing olopatadine hydrochloride with significant efficacy, good taste, good patient compliance, good stability, simple preparation process, and low cost, along with its preparation method, is imperative and has broad market value and application prospects. It is of great significance to promoting the development of the olopatadine hydrochloride formulation field. To this end, an olopatadine orally rapidly disintegrating tablet composition and its preparation method are provided. Summary of the Invention

[0007] The purpose of this invention is to address the deficiencies of the prior art by providing an olopatadine orally rapidly disintegrating tablet composition and its preparation method, thereby solving the problems mentioned in the background art.

[0008] To achieve the above objectives, the present invention provides the following technical solution: an olopatadine orally rapidly disintegrating tablet composition, wherein the composition comprises olopatadine, mannitol, a flavor masking agent, a disintegrant, a flavoring agent, colloidal silica, and magnesium stearate;

[0009] By weight percentage, olopatadine accounts for 1.0-10.0%, mannitol accounts for 30.0-90.0%, flavor masking agent accounts for 0.01-1.0%, flavoring agent accounts for 0.01-1.0%, disintegrant accounts for 1.0-10.0%, colloidal silica accounts for 0.5-5.0%, and magnesium stearate accounts for 0.5-15.0%.

[0010] As a preferred embodiment of the present invention, the flavor masking agent is a methacrylic acid copolymer.

[0011] As a preferred embodiment of the present invention, the flavoring agent is any one or more combinations of neotame, sucralose and flavoring.

[0012] As a preferred embodiment of the present invention, the disintegrant is any one or more combinations of crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose.

[0013] As a preferred embodiment of the present invention, the mannitol is mannitol 200SD.

[0014] A method for preparing the olopatadine orally rapidly disintegrating tablet composition as described above includes the following steps:

[0015] Step 1: Pre-treat olopatadine to control particle size. Olopatadine D 90 Controlled to 10~150μm;

[0016] Step 2: Sift and mix olopatadine and the masking agent;

[0017] Step 3: Add the flavoring agent to the materials from Step 2 and continue sieving and mixing;

[0018] Step 4: Mix mannitol with colloidal silica and disintegrant, and then sieve.

[0019] Step 5: After mixing the mixture from Step 3 and Step 4, add magnesium stearate and then compress the mixture into tablets.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] This invention provides an orally disintegrating tablet of olopatadine and its preparation method. The formulation comprises the active ingredient olopatadine, mannitol, a taste mask, a disintegrant, a flavoring agent, colloidal silica, and magnesium stearate. The composition prepared using this formulation can improve the stability of the drug, has an in vitro dissolution profile consistent with the reference formulation, and has a good taste, increasing palatability for patients during administration.

[0022] Compared to the three-step granulation process used in the original Allelock product, this invention innovatively adopts a step-by-step mixing process: first, the active pharmaceutical ingredient (API) is premixed with a flavoring agent, then mixed with a flavoring agent, and finally mixed with other excipients and directly compressed into tablets. This process has the following outstanding advantages: (1) the preparation process is significantly simplified and the production cost is greatly reduced; (2) the resulting tablets have good oral palatability and significantly improve patient compliance; (3) the in vitro quality indicators and stability are consistent with the original Allelock product. This invention provides a more industrially advantageous preparation scheme for olopatadine formulation. Attached Figure Description

[0023] Figure 1 This is a dissolution curve of the self-made product and the reference product in an aqueous medium in Example 2 of the present invention. Detailed Implementation

[0024] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0025] This invention provides a technical solution: an olopatadine orally rapidly disintegrating tablet composition, the composition comprising olopatadine, mannitol, flavor masking agent, disintegrant, flavoring agent, colloidal silica and magnesium stearate;

[0026] By weight percentage, olopatadine accounts for 1.0-10.0%, mannitol accounts for 30.0-90.0%, flavor masking agent accounts for 0.01-1.0%, flavoring agent accounts for 0.01-1.0%, disintegrant accounts for 1.0-10.0%, colloidal silica accounts for 0.5-5.0%, and magnesium stearate accounts for 0.5-15.0%.

[0027] The masking agent is a copolymer of methacrylic acid.

[0028] The flavoring agent is any one or more combinations of neotame, sucralose, and flavoring.

[0029] The disintegrant is any one or more combinations of crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose.

[0030] A method for preparing the olopatadine orally rapidly disintegrating tablet composition as described above includes the following steps:

[0031] Step 1: Pre-treat olopatadine to control particle size. Olopatadine D 90 Controlled to 10~150μm;

[0032] Step 2: Sift and mix olopatadine and the masking agent;

[0033] Step 3: Add the flavoring agent to the materials from Step 2 and continue sieving and mixing;

[0034] Step 4: Mix mannitol with colloidal silica and disintegrant, and then sieve.

[0035] Step 5: After mixing the mixture from Step 3 and Step 4, add magnesium stearate and then compress the mixture into tablets.

[0036] Example 1: The prescription composition is shown in Table 1:

[0037] Table 1: Composition of Prescriptions 1-4

[0038]

[0039] Preparation method: According to the preparation process of the present invention, the prescribed amounts of raw and excipient materials are weighed, mixed evenly, and then tableted.

[0040] Verification Example 1:

[0041] Taste test: Ten volunteers (five men and five women) were randomly selected for a blind taste test. They tasted the samples in turn and rinsed their mouths with drinking water until there was no residual taste of the previous drug before testing the next one. The taste was ranked and scored according to taste, as shown in Table 2. The best taste was 10 points and the worst taste was 1 point.

[0042] Table 2: Taste Test Tables for Prescriptions 1-4 and Reference

[0043]

[0044] Conclusion: Formulas 1-3 had slightly inferior aroma, sweetness, and aftertaste compared to the reference formulation, while Formula 4 had the same taste as the reference formulation.

[0045] Example 2: The prescription composition is shown in Table 3:

[0046] Table 3: Composition of Prescriptions 5-10

[0047]

[0048] Preparation method: Weigh the prescribed amount of raw and excipient materials for formulation 5-7 and perform wet granulation. After drying, granulate, add magnesium stearate for total mixing, and then compress into tablets.

[0049] For prescription 8-10, weigh out the prescribed amount of raw and excipient materials, mix them evenly, add magnesium stearate for total mixing, and then compress into tablets.

[0050] The stability data is summarized in Table 4.

[0051] Table 4: Summary Table of Stability Data

[0052]

[0053] Conclusion: Combining Table 4 and Figure 1 As shown, formulations 5-7 use a wet granulation process, and the impurity increase trend during the stability stage is slightly faster than that of the reference formulation. In the stability stage of formulations 8-9, the impurity increase trend is consistent with that of the reference formulation, but the disintegration time does not meet the requirements. In the stability stage of formulation 10, the impurity increase trend is consistent with that of the reference formulation, and the disintegration time meets the requirements.

[0054] The above embodiments merely illustrate implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A composition for olopatadine orally rapidly disintegrating tablets, characterized in that: The composition comprises olopatadine, mannitol, flavor masking agent, disintegrant, flavoring agent, colloidal silica, and magnesium stearate; By weight percentage, the content of olopatadine is 1.0–10.0%, mannitol is 30.0–90.0%, flavor masking agent is 0.01–1.0%, flavoring agent is 0.01–1.0%, disintegrant is 1.0–10.0%, colloidal silica is 0.5–5.0%, and magnesium stearate is 0.5–15.0%. The flavor masking agent is a copolymer of methacrylic acid; The flavoring agents are neotame and peppermint flavoring; The disintegrants are carboxymethyl cellulose and crospovidone; The specific preparation method is as follows: Step 1: Pre-treat olopatadine to control particle size. Olopatadine D 90 Controlled within 10–150 μm; Step 2: Sift and mix olopatadine and the masking agent; Step 3: Add the flavoring agent to the materials from Step 2 and continue sieving and mixing; Step 4: Mix mannitol with colloidal silica and disintegrant, and then sieve. Step 5: After mixing the mixture from Step 3 and Step 4, add magnesium stearate and then compress the mixture into tablets.

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

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