CN-121985940-A - Method for producing an oral osmotic drug delivery system and drug lot produced using the method

Abstract

A method of producing an oral osmotic drug delivery system using statistical modeling. The method includes determining a desired average dissolution profile of the active pharmaceutical ingredient and controlling tablet strength, acetyl content of cellulose acetate and weight gain of the semipermeable membrane of the tablet to produce a batch of tablet drug having the desired dissolution profile.

Inventors

• C.CHANG
• STATON JOHN
• D. Chela
• K. Polovi ć
• M. Camp
• H. P. Kaito

Assignees

• 联合治疗公司

Dates

Publication Date

20260505

Application Date

20240807

Priority Date

20230808

Claims (20)

1. 1. A method of producing a pharmaceutical batch of a controlled release pharmaceutical composition, wherein the controlled release pharmaceutical composition is a tablet comprising a core comprising an active pharmaceutical ingredient surrounded by a semipermeable membrane comprising cellulose acetate and an outer coating, the method comprising: Determining a desired average dissolution profile of said active pharmaceutical ingredient, and Tablet strength, acetyl content of the cellulose acetate and weight gain of the semipermeable membrane of the tablet are controlled to produce a tablet drug lot having a desired dissolution profile.
2. 2. The method of claim 1, wherein the result of the desired average dissolution is determined at 6 hours.
3. 3. The method of claim 1, wherein the amount of the active pharmaceutical ingredient is from 0.125 mg to 5 mg per tablet.
4. 4. A method according to claim 3, wherein the active pharmaceutical ingredient is treprostinil diethanolamine.
5. 5. The method of claim 1, wherein the acetyl content is 39.3% to 40.3%.
6. 6. The method of claim 1, wherein the desired weight gain of the semipermeable membrane is 3.2% w/w to 4.1% w/w.
7. 7. The method of claim 1, wherein the percentage of drug batches that do not meet a desired average dissolution result is less than 4.2%.
8. 8. A pharmaceutical batch produced by the method of claim 1.
9. 9. The pharmaceutical batch of claim 8, wherein the amount of active pharmaceutical ingredient is from 0.125 mg to 5 mg per tablet.
10. 10. The pharmaceutical batch of claim 8, wherein the acetyl content is 39.3% to 40.3%.
11. 11. The pharmaceutical batch of claim 10, wherein the active pharmaceutical ingredient is treprostinil diethanolamine.
12. 12. The pharmaceutical batch of claim 11, wherein the semipermeable membrane comprises an opening adapted for laser drilling for osmotic delivery.
13. 13. The pharmaceutical batch of claim 12, wherein the tablet further comprises: A) At least one release enhancer selected from the group consisting of a wicking agent, a complexing agent, and a micelle forming agent, wherein I) The wicking agent is selected from the group consisting of high HLB surfactants, ionic surfactants and non-swelling hydrophilic polymers, Ii) the complexing agent is selected from the group consisting of polyvinylpyrrolidone, cyclodextrin and nonionic surfactant, and Iii) The micelle forming agent is selected from the group consisting of poly (ethylene oxide) modified sorbitan monoesters, sorbitan fatty acid esters, sodium lauryl sulfate, and sodium docusate.
14. 14. A method of producing a pharmaceutical batch of a controlled release pharmaceutical solid dosage form comprising cores comprising an active pharmaceutical ingredient surrounded by a semipermeable membrane comprising cellulose acetate, the method comprising (a) selecting an amount of active pharmaceutical ingredient of the solid dosage form, (b) producing a batch of cores each comprising the active pharmaceutical ingredient in the selected amount, (c) obtaining a batch of cellulose acetate, (d) determining the content of acetyl groups in the obtained batch, (e) determining an effective coating amount based on the selected amount of active pharmaceutical ingredient and the determined content of acetyl groups, from statistics of previously produced pharmaceutical batches for the selected amount of active ingredient, and (f) for each core in the batch, forming a semipermeable membrane coating around the core using the effective coating amount determined in step (e).
15. 15. The method of claim 14, wherein the active pharmaceutical ingredient is treprostinil or its salt.
16. 16. The method of claim 15, wherein the active pharmaceutical ingredient is a salt of treprostinil.
17. 17. The method of claim 16, wherein the salt of treprostinil is treprostinil diethanolamine.
18. 18. The method of claim 17, wherein the selecting comprises selecting an amount of treprostinil diethanolamine corresponding to an amount of treprostinil of 0.125 mg to 5 mg.
19. 19. The method of claim 18, wherein the selecting comprises selecting an amount of treprostinil corresponding to an amount of treprostinil selected from the group consisting of 0.125 mg, 0.25 mg, 1mg, 2.5 mg, and 5 mg.
20. 20. The method according to any one of claims 14 to 19, wherein the determined content in the obtained batch is 39.3% to 40.3%.

Description

Method for producing an oral osmotic drug delivery system and drug lot produced using the method Cross Reference to Related Applications The present application claims priority from U.S. provisional application 63/531,428 filed 8 at 2023, 8, which is incorporated herein by reference in its entirety. Background The present disclosure relates generally to the field of sustained release (extended release) oral tablet manufacturing. More specifically, the present disclosure relates to the use of statistical modeling in the manufacture of sustained release oral tablets for drug osmotic delivery using a semipermeable membrane comprising cellulose acetate. Sustained release tablets having an osmotically active drug core surrounded by a semipermeable membrane are known in the art. The function of these osmotic dosage forms is to allow water from gastric or intestinal fluids to pass through the semi-permeable membrane and dissolve the active ingredient in the core, thereby allowing it to be released through one or more channels in the membrane. Primary osmotic pump (ELEMENTARY OSMOTIC PUMP, EOP) delivery systems require that the drug be in solution for delivery in a controlled and predictable manner. The drug solution is pumped out due to the osmotic gradient created across the semipermeable membrane. The solubility of a drug in an aqueous medium is often used as a reference to evaluate whether a solubilizer is needed in a core formulation. To overcome the challenge of limited solubility of poorly soluble drugs, a variety of drug delivery platforms have been developed. If the drug is insoluble, the primary osmotic pump system will not function properly. Kuczynski et al (U.S. patent 5,545,413) developed a method of delivering an agent that is insoluble in an aqueous solvent. In their method, the interior of a tablet or capsule is characterized by having two core layers, one containing the agent (which will be released through openings or holes in the tablet or capsule wall) and the other being a layer of material that swells upon contact with water. Materials that swell or expand to an equilibrium state upon exposure to water or other biological fluids are referred to as "osmopolymers (osmopolymer)". This volume expansion serves to physically force the medicament out through openings formed in the wall, shell or coating during manufacture. The pharmaceutical agents are mainly released in the form of insoluble particles and thus have limited bioavailability. This method is commonly referred to as the "push/pull" method. See, for example, U.S. Pat. Nos. 5,422,123, 4,783,337, 4,765,989, 4,612,008, and 4,327,725. The patent literature teaches such a method for delivering sufficient doses of multiple drugs at a controlled rate and for an extended period of time. Other osmotic delivery systems have also been described. See, for example, U.S. Pat. Nos. 4,609,374, 4,036,228, 4,992,278, 4,160,020, and 4,615,698. Osmopolymers used in these types of systems are components that function by swelling as they interact with water and aqueous fluids. This swelling effect is defined in these patents as the characteristic of volume expansion to an extremely high degree upon fluid absorption, typically exhibiting a2 to 50-fold volume increase. Rudnic et al (U.S. Pat. nos. 6,110,498;6,284,276;6,361,796 and 6,514,532) use sodium lauryl sulfate and other solubilizing agents to increase the solubility of the poorly soluble drug glipizide (glipizide) in order to deliver the drug in a sustained manner from a primary type osmotic system. This system of Rudnic comprises (a) a semipermeable wall that maintains its integrity during drug delivery and that has at least one passageway therethrough, (b) a single homogeneous composition within said wall, said composition consisting essentially of (i) a pharmaceutically active agent, (ii) at least one non-swelling solubilizing agent that enhances the solubility of said pharmaceutically active agent, (iii) at least one non-swelling osmotic agent, and optionally (iv) a non-swelling wicking agent dispersed throughout the composition that enhances surface area contact of the agent with an incoming aqueous fluid. Thombre et al (U.S. patent 5,697,922) used meglumine as a solubilizing agent for glipizide. The patent proposes coating meglumine with a semipermeable polymer film to prolong the release of the solubilizing agent from the core. Thombre et al believe that the non-encapsulated solubilizing agent will prematurely leave the core, leaving the drug in undissolved form. This loss of solubilizer results in an unstable release or no release at all. The problem with this approach is that it is very complex because it involves the coating of the solubilizing excipient during the tablet manufacturing process. This process limits its practical value. Furthermore, the amount of solubilizing excipient used in this process is very high. See also U.S. Pat. No. 5,698,220, which discloses the use of 90% meglumine (al