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Extended release formulations for intra-articular applications

A composition and drug technology, applied in the field of extended release formulations, can solve the problems of frequent injection, short synovial residence half-life and the like

Pending Publication Date: 2020-06-12
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, immediate release formulations have a short synovial residence half-life and require frequent injections due to the high fluid exchange between synovial fluid and blood stream

Method used

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  • Extended release formulations for intra-articular applications
  • Extended release formulations for intra-articular applications
  • Extended release formulations for intra-articular applications

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0131] Example 1. Preparation of Microcrystals of Compound A

[0132] The production batch of Compound A was observed under an electron microscope ( figure 1 ). The particles are irregular and columnar and range in length from about 100 nm up to 140 μm, but most particles are smaller than 50 μm. These particles have a tendency to agglomerate.

[0133] Compound A can be micronized using any method known to those skilled in the art. The unmilled compound A was subjected to a size reduction process to obtain particle size. The size reduction of Compound A can be performed using any known method, such as by jet milling techniques, and more specifically, by spiral jet milling techniques, fluidized bed opposed jet milling techniques, or annular jet milling techniques.

[0134] In one embodiment, the particle size distribution of Compound A is D90≦50 μm. In another embodiment, Compound A has a particle size distribution of D90 < 30 μm, < 25 μm, < 20 μm or < 15 μm.

[0135] In...

example 2

[0138] Example 2. Formulation Screening with PVP-K12 or CMC

[0139] A microcrystalline suspension of Compound A prepared in Example 1 was prepared with a solution containing PVP-K12 or carboxymethylcellulose (CMC) sodium salt. The resuspension of the formulation was tested by repeated centrifugation and shaking resuspension. Formulations containing CMC were not resuspended after centrifugation. Formulations containing PVP-K12 were further investigated.

example 3

[0140] Example 3. Formulations P1-P8 (PVP-K12 with F68, F127, SDS or egg PC)

[0141] Placebo solutions P1 to P8 were prepared according to the ingredients (w / v %) listed in Table 2.

[0142] Table 2

[0143] Preparations PVP-K12(%) additional excipients Additional excipients (%) P1 2％ F68 0.2％ P2 2％ F68 0.5％ P3 2％ F127 0.2％ P4 2％ F127 0.5％ P5 2％ SDS 0.05％ P6 2％ SDS 0.01％ P7 2％ Egg PC 0.2％ P8 2％ Egg PC 0.5％

[0144] Formulations were prepared in R2 vials containing approximately 5 mg of Compound A microcrystals and filled with placebo solutions P1 to P8 to achieve a drug substance concentration of 5 mg / mL. The formulations were tested for resuspension and sedimentation rate according to the sequential steps listed in column 1 of Table 3. After each step, the turbidity of the samples was observed and documented by photographs and is summarized in Table 3.

[0145] table 3

[0146]

[0147] ...

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Abstract

The present invention relates to a pharmaceutical composition comprising an aqueous suspension of: (i) crystalline N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane- 2-carboxamide ora pharmaceutically acceptable salt thereof; and (ii) a surfactant comprising a water-soluble co-polymer characterized by > 5% solubility in water at 25 DEG C. The compositions provide extended releaseof N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1] heptane- 2-carboxamide, and are suitable for intra-articular injection to a joint of a patient suffering from arthritis, joint injury orcartilage injury.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 584,589, filed November 10, 2017, and U.S. Provisional Application Serial No. 62 / 743,864, filed October 10, 2018; each of which is hereby incorporated by reference in its entirety . technical field [0003] The present invention relates to extended release formulations for the treatment or prevention of joint damage caused by arthritis, joint damage and cartilage damage. Background technique [0004] Arthritis is inflammation of one or more joints and affects approximately 350 million people worldwide. Osteoarthritis (OA) is the most common form of arthritis and is characterized by the slow degenerative destruction of joints including both the articular cartilage and the subchondral bone underlying the articular cartilage. Joint damage (eg, acute joint injury, such as a meniscal or ligament tear, or an intra-articular fracture) can also...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K8/22A61K31/4465A61K9/00A61K47/10A61P19/02
CPCA61K9/0019A61K47/10A61P19/02A61K45/06A61K31/443A61K2300/00A61K31/4525A61K9/08A61K47/20A61K47/32A61K47/34A61K31/4465
Inventor C·卡斯塔尼奥利A·菲施M·洛舍德M·L·尼哈卡B·U·里贝瑟尔
Owner NOVARTIS AG
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