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Tofacitinib or tofacitinib salt sustained release preparation and preparation method thereof

A sustained-release preparation, tofacitinib technology, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, pill delivery, etc., can solve incomplete drug release, reduced solubility, and low melting point of sorbitol and other problems to achieve the effect of avoiding the "pan-JAK" inhibition effect and good stability

Pending Publication Date: 2020-10-02
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is a certain problem of incomplete absorption in the tofacitinib sustained-release formulation, and the bioequivalent specification of the 10mg immediate-release formulation is adjusted to 11mg
In addition, the tofacitinib sustained-release preparation uses sorbitol as an osmogen to prepare osmotic pump tablets. The melting point of sorbitol is low, and the preparation process requires special control of humidity, which brings certain challenges to the industrial production process of the product.
[0024] In summary, in view of the fact that the solubility of tofacitinib decreases with the increase of the pH value, the preparation of sustained-release preparations of tofacitinib has the following common problems: the usual sustained-release preparations are due to the prolongation of drug release time, and the drug remains in the intestinal tract (jejunum). , ileum, colon) during the continuous drug release process, due to the gradual decrease of water in the lower part of the digestive tract, in addition, the solubility of tofacitinib decreases significantly with the increase of pH value, which easily leads to incomplete drug release. Absorption of tib in the lower digestive tract

Method used

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  • Tofacitinib or tofacitinib salt sustained release preparation and preparation method thereof
  • Tofacitinib or tofacitinib salt sustained release preparation and preparation method thereof
  • Tofacitinib or tofacitinib salt sustained release preparation and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0083] 1. Prescription

[0084] The compositions of the ingredients in the sustained-release formulations of prescriptions 1-16 are shown in Tables 1-3 below.

[0085] Table 1 Composition of ingredients in the sustained-release preparations of prescriptions 1-6

[0086]

[0087] Table 2 Composition of each ingredient in the sustained-release preparations of prescriptions 7-11

[0088]

[0089] Table 3 Composition of ingredients in the sustained-release preparations of prescriptions 12-16

[0090]

[0091] 2. Preparation method

[0092] The sustained-release preparation of tofacitinib or its salt of the present invention comprises the following preparation steps according to the sequence of the preparation process: (1) preparation of the drug-containing composition and the osmotic tablet core; (2) optional sealing isolation coat coating ; (3) release-controlling coating; (4) perforation of the coated tablet; and optionally, (5) aesthetic coating.

[0093] (1) Table...

experiment Embodiment 1

[0113] Experimental Example 1: Determination of the release rate of prescriptions 1 to 16

[0114] Using the second method device of the dissolution and release test method (general rule 0931), put the osmotic pump tablet in the sedimentation basket, use 900mL of pH6.8 phosphate buffer as the release medium, and operate according to the law at a speed of 50rpm. After 1, 2.5 , 4, 6, 8, and 10 hours each take 5 mL of the solution, and replenish the release medium at the same temperature and volume in time. Get sample solution, centrifuge (8000rpm, 10min), get supernatant as need testing solution. Another appropriate amount of tofacitinib citrate reference substance was taken, accurately weighed, dissolved in a release medium and quantitatively diluted to make about 12 μg of tofacitinib citrate per 1 ml, as a reference solution. According to the high-performance liquid chromatography (general rule 0512), each 10 μ l of the above-mentioned reference substance solution and need te...

experiment Embodiment 2

[0123] Experimental Example 2: Comparison of Release Behavior of Prescription 11 and Commercially Available Sustained-release Preparations in Different pH Media

[0124] Due to the solubility of drugs under different pH conditions, the hydration, swelling, and erosion rates of key excipients that control drug release behavior may be different. Therefore, the drug release behavior of formulation 11 in Preparation Example 1 and the commercially available sustained-release preparation in release media with different pH values ​​was investigated.

[0125] Using the second method device of the dissolution and release assay method (general rule 0931), put the osmotic pump tablet in the sedimentation basket, and use 900mL of release media with different pH values ​​(including ①pH1.2 hydrochloric acid solution; ②pH4.5 phosphate buffer; ③pH6.8 phosphate buffer solution; ④pH7.4 phosphate buffer solution), the rotating speed is 50rpm, operate according to the law, after 1, 2.5, 4, 6, 8, ...

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Abstract

The present invention relates to a tofacitinib or tofacitinib salt sustained release preparation, which sequentially comprises a permeation tablet core composition containing a release accelerant, a controlled release coating, and an unnecessary aesthetic coat from inside to outside, wherein based on the total weight of the tablet core composition, the tablet core composition comprises 6.4wt%-16wt% of a pharmaceutical active component, 20wt%-77wt% of the release accelerant, 0wt%-56wt% of an osmotic pressure accelerant, 16wt%-50wt% of an adhesive and 0.5wt%-7wt% of other pharmaceutical auxiliary materials; and the release accelerant is a cyclic oligosaccharide cyclodextrin derivative. The tofacitinib sustained release preparation prepared from the osmotic tablet core composition containingthe release accelerant can increase the in-vivo exposure amount of tofacitinib and has improved bioavailability.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to the field of drug sustained-release preparations, in particular to a sustained-release preparation of tofacitinib or a salt thereof and a preparation method thereof. Background technique [0002] Rheumatoid Arthritis (Rheumatoid Arthritis, RA) is a common chronic, inflammatory, systemic autoimmune disease, also known as "undead cancer". The clinical pathological features of RA are mainly manifested in three aspects: ① local inflammatory cell infiltration in joints triggers chronic inflammation; ② synovial cell infiltration and growth in joints leads to synovial thickening; ③ bone erosion and cartilage tissue damage lead to joint deformities and loss of function. [0003] The pathogenesis of RA is still unclear, but it is presumed to be a "prime-chain" reaction driven by antigens. Epidemiological surveys show that the global incidence of RA is 0.5% to 1%, and the incid...

Claims

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Application Information

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IPC IPC(8): A61K9/36A61K31/519A61K47/69A61P19/02A61P37/02
CPCA61K31/519A61K47/6951A61P19/02A61P37/02A61K9/2886A61K9/2866
Inventor 甘勇朱春柳朱全垒
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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