Clotting factor preparations for delivery into tissue of the intestinal tract using a swallowable drug delivery device

A preparation and factor technology, applied in the field of pharmaceutical preparations that can be delivered orally in a stable form of factor VIII, can solve the problems of increased immunogenicity and increased production of inhibitory antibodies, etc.

Pending Publication Date: 2022-02-01
RANI THERAPEUTICS
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Another concern is the increased immunogenicity of the SC route compared to IV, which may lead

Method used

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  • Clotting factor preparations for delivery into tissue of the intestinal tract using a swallowable drug delivery device
  • Clotting factor preparations for delivery into tissue of the intestinal tract using a swallowable drug delivery device
  • Clotting factor preparations for delivery into tissue of the intestinal tract using a swallowable drug delivery device

Examples

Experimental program
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Embodiment approach

[0264] In a specific embodiment, the invention provides therapeutic formulations for the treatment of coagulation disorders comprising a stabilized form of Factor VIII (or other coagulation factors) to increase the drug's circulating half-life and thereby increase its AUC and bioavailability. Stabilization can be achieved by one or both of the following methods: i) chemically complexing a given type of Factor VIII (e.g., wild-type or recombinant) with a stabilizer, or ii) in a therapeutic formulation comprising Factor VIII 100 comprising an excipient comprising a stabilizer. Examples of chemical complexation methods and reagents include pegylation, where FVIII molecules are complexed with PEG molecules, or via Fc fusion, both of which are described in more detail herein. Other stabilizers for chemical complexation are also contemplated, including, for example, von Willebrand factor or one or more hydrogels.

[0265]In various embodiments, stabilizers / excipients may be heterog...

Embodiment 1

[0391] Example 1: In vivo modeling of Factor VIII delivery in humans using an embodiment of the swallowable device described herein

[0392] A pharmacokinetic model was developed to determine human plasma concentration versus time profiles (also described as plasma-time curve or plasma concentration curve) and various pharmacokinetic parameters, including but not limited to T max , T1 / 2, area under the curve (AUC) and absolute bioavailability (F, expressed as a percentage). The model assumes a delivered dose of 100 IU / kg body weight for each drug. Numerical results for PEGylated FVIII (eg, ADYNOVATE) and specifically for ESPEROCT are shown in Tables 6 and 7, respectively. With the exception of bioavailability, the range for each parameter is assumed to be ±25% of the nominal value, with a narrower range of ±10%. The plasma concentration-time profiles of PEGylated FVIII and ESPEROCT are specifically shown in Figures 22 and 23, respectively. The ±25% range shown for each cur...

Embodiment 2

[0399] Example 2: In vivo canine study of PEGylated FVIII delivery

[0400] Purpose: The purpose of the study was to demonstrate peritoneal delivery of the Factor VIII molecule in conscious hemophiliac dogs and to assess the bioavailability of delivery in the peritoneum as Factor VIII via the embodiments and / or variants of the swallowable capsules described herein. Proof of concept study of delivery to the peritoneal cavity. PEGylated FVIII was used as a representative of the Factor VIII molecular class.

[0401] Materials and methods

[0402] Dogs with hemophilia A (Irish Setters) were injected intravenously (IV) and intraperitoneally (IP) with pegylated FVIII. The study was divided into three parts (Part 1, Part 2, Part 3) that varied by dose, time of delivery (days) and type of delivery (IP vs IV). For this example, doses are expressed in IU / kg, it being understood that kg refers to kg of body weight.

[0403] In part 1, dogs received 300 IU / kg by IP route on day 0 (IP ...

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Abstract

Embodiments provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs), e.g., Factor VIII (FVIII) including PEGylated and other forms of stabilized FVIII, within the GI tract. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations configured to be contained within the capsule, advanced from the capsule into the IW and/or surrounding tissue (ST) and degrade to release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivery of CFs for treatment of clotting disorders (e.g., hemophilia) where such CFs are poorly absorbed and/or degraded within the GI tract.

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit to U.S. Provisional Patent Applications Serial No. 62 / 843,221, filed May 3, 2019, and Serial No. 62 / 845,209, filed May 8, 2019, both of which are incorporated by reference for all purposes Incorporated into this article as a whole. Background technique [0003] technical field . Embodiments of the present invention relate to orally deliverable drug and other therapeutic agent formulations and swallowable drug delivery devices for delivering these formulations to the lumen wall of the gastrointestinal tract, such as the small intestine wall or surrounding tissue. More specifically, embodiments of the present invention relate to orally deliverable pharmaceutical formulations for the treatment of coagulation disorders. More specifically, embodiments of the invention relate to orally deliverable solid pharmaceutical formulations for the treatment of hemophilia and von Willebr...

Claims

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Application Information

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IPC IPC(8): A61K38/37A61K9/22A61K38/36A61P7/04C07K14/55
CPCA61K38/37A61P7/04A61K47/60A61M2005/14284A61M5/14276A61M2205/6072A61M5/3295A61M5/31565A61M2205/3507A61K47/6811A61M31/002A61K9/0053A61M37/0015A61M2037/0023
Inventor 米尔·A·伊姆兰萨拉·安萨罗尼瑞德黑卡·科鲁波鲁乔尔·哈利斯米尔·哈什姆阿努莎·加拉帕蒂安维什·达萨里
Owner RANI THERAPEUTICS
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