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Liposomal composition containing mild acidic active agent

Inactive Publication Date: 2019-05-30
TLC BIOPHARMACEUTICALS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a solution for improving the inconvenience treatment of conventional prostaglandins by providing a liposomal composition containing Prostaglandin E1 (PGE1). The liposomal formulation allows for gradual release of PGE1 from liposomes, reducing the side effect and allowing for increased dosage without gaining serious side effect problem. The delivery vehicle, kit, and method provide a more friendly and convenient product for patient usage. The goal is to establish a ready-to-use liposomal composition with high encapsulation efficiency, stable storage, and animal model efficacy.

Problems solved by technology

Weak acid drugs, such as prostaglandins (PGs), have disadvantages for pharmaceutical use.
However, due to the short half life in human body of PGE1 (about 30 seconds) and its serious side effect when being overdosed, a high frequency of administrating limited dose remains necessary in treatment of PGE1-CD.
However, the stability on shelf or in plasma of such preparations is not sufficient (U.S. Pat. No. 4,684,633).
However, this conventional liposomal dispersion is prepared by passive loading with a non-ensured encapsulation efficiency of PG.
Unentrapped PG could lead to overdose problems during its administration to a subject.
However, little is proven to be applicable for loading or encapsulating weak acid drugs in PEG-derivatized liposomes with a prompt procedure under ambient temperature for ease of clinical use.
However, based on the previous technique for loading a weak acid drug into liposomes or stealth liposomes in conjunction with an experimental data (FIG. 1) conducted by the Applicants, it demonstrates that stealth liposomes possess poor encapsulation efficiency at an ambient temperature (25° C.) and require a heating step to increase permeability of prostaglandins.
The elevated temperature accelerates the degradation of labile drug, such as prostaglandins, when being exposed to an aqueous environment, and thus hampers the stability of the composition in long term storage.
However, the conventional treatment with PGE1-CD (alpha-cyclodextrin form) is inconvenience for patients in a regimen of BID (twice a day) for weeks.
Higher encapsulation efficiency reduces free form of the agent which could cause undesired side effect while overdosed.

Method used

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  • Liposomal composition containing mild acidic active agent
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Examples

Experimental program
Comparison scheme
Effect test

example 1

Process for Preparing Lyophilized Cake

[0073]Cryoprotectant was dissolved in hot water (50˜60° C.) and then cooled to below 40° C. to form a cryoprotectant solution. Prostaglandin E1 was dissolved in tert-Butyl alcohol (TBA) being pre-warmed to liquefy the solvent at 40° C. and then transferred to and mixed with the cryoprotectant solution to form a prostaglandin solution. The prostaglandin solution was subjected to aseptic filtration and filled into 6R vial, followed by lyophilization to form a lyophilized cake containing PGE1 (hereby also denoted as alprostadil cake). The lyophilization was performed with a shelf lyophilizer under a program with the parameters as listed in the below Table I.

TABLE IThe lyophilization parameters for alprostadil cakeFreezePrimary dryingSecondary dryingEndtemperature (° C.)−40−40−30304duration (min)902403000720—pressure (mTorr)——100100100

example 2

Preparation of Alprostadil Cake with Various Components

[0074]To find a suitable formulation for forming the alprostadil cake according to the present disclosure, 52.6 μg PGE1 per vial was proposed for alprostadil cake, 125 mg cryoprotectant was used for our formulation.

[0075]As PGE1 was used as API in the formulation, a suitable solvent was needed to dissolve water-insoluble PGE1. PGE1 is soluble in tert-Butyl alcohol (TBA). TBA was selected to dissolve PGE1 to form the prostaglandin solution.

[0076]PGE1 undergo dehydration to form prostaglandin A1. In order to increase the shelf life of PGE1, lyophilization was used to reduce the moisture content to a very low level to minimize the degradation. Screening of the candidate formulations were based on results of 40° C. accelerated stability test.

[0077]As the content of cryoprotectant and PGE1 per vial was fixed as above, the other lyophilization parameters, such as water content, TBA addition or others were further modulated as describe...

example 2a

Effect of Water Content in the Prostaglandin Solution

[0078]First, upon the fixed percentage of TBA, the effect of percentage of water before lyophilization was investigated by using the formulations as listed in Table III to form the alprostadil cakes.

TABLE IIIFormulations of the prostaglandin solutions with various water contentComposition per vial: mg (% (w:w))FormulationlactoseCodePGE1*TBAmonohydratewaterPc0290.052613.8 (1.02)125 (9.26) 1211.1 (89.71)(0.0039)Pc0300.052610.8 (1.02)125 (11.90) 914.2 (87.07)(0.0050)Pc0310.0526 9.2 (1.02)125 (13.89) 765.7 (85.08)(0.0058)Pc0320.0526 7.7 (1.02)125 (16.67) 617.3 (82.30)(0.0070)*52.6 μg instead of 50 μg of PGE1 was used hereby to adjust the final concentration of PGE1 after reconstitution by 5 mL liposome solution to be 10 μg / mL

[0079]As shown in Table IV, all formulations met the criteria of 90% PGE1 remaining after 6 weeks at 40° C., the remaining content decreased as percentage of water in the prostaglandin solution decreased. It demon...

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Abstract

Provided is a method for preparing a liposomal composition. The method comprises the step of contacting a liposome solution with a mild acidic agent for a limited time. The liposome solution comprises a weak acid salt encapsulated within an aqueous interior space separated from the aqueous medium by a membrane comprised of a lipid mixture containing one or more lipids and a hydrophilic polymer conjugated lipid at a molar percentage of less than 3% based on the total amount of the lipid mixture. The time for encapsulating the agent to a desired amount at a predetermined ratio to lipids is dramatically reduced even under a condition without elevating the temperature to above ambient environment.

Description

BACKGROUND1. Technical Field[0001]The present disclosure relates to a delivery vehicle, kit or method for preparing liposomes encapsulating a therapeutic agent, particularly a weak acid drug.2. Description of Related Art[0002]There have been many approaches to improving the stability or other properties in association with therapeutic functions of a weak acid drug. Weak acid drugs, such as prostaglandins (PGs), have disadvantages for pharmaceutical use. For example, Edex® is a sterile, pyrogen-free powder containing in alpha-cyclodextrin inclusion complex, also known as an alpha-cyclodextrin form of prostaglandin E1 (PGE1-CD). It is freely soluble in water and practically insoluble in ethanol, ethyl acetate and ether. After reconstitution, the active ingredient, alprostadil, immediately dissociates from the α-cyclodextrin inclusion complex. However, due to the short half life in human body of PGE1 (about 30 seconds) and its serious side effect when being overdosed, a high frequency ...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/5575A61K47/12
CPCA61K9/1271A61K31/5575A61K47/12A61P1/04A61P11/06A61P15/04A61P9/08A61P9/12
Inventor HUANG, KE-MINGCHEN, HE-RUHONG, KEELUNG
Owner TLC BIOPHARMACEUTICALS INC
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