Use of PEG-based interpolymer complexes for improved solubilization of BCS class II drugs

Abstract

The present invention includes a method for improving the water solubility of an active pharmaceutical ingredient classified in Class II of the Biopharmaceutics Classification System. The method includes mixing polyethylene glycol with polyacrylic acid in water under conditions sufficient to form at least some interpolymer complexes, and then adding the active pharmaceutical ingredient to the mixture.

Description

Technical Field

[0001] The present invention includes a method for improving the water solubility of an active pharmaceutical ingredient classified in Class II of the Biopharmaceutics Classification System.

Background Art

[0002] Solubility, dissolution, and gastrointestinal permeability are fundamental parameters that control the rate and extent of drug absorption and its bioavailability. The aqueous solubility of a drug plays an important role in drug absorption after oral administration. Insufficient aqueous solubility of the active pharmaceutical ingredient is a significant challenge in the development process of new drug formulations. Poor water solubility hinders the bioavailability of the drug and reduces its pharmaceutical development. The pharmaceutical development of drugs with poor water solubility requires, among other techniques, the establishment of a suitable formulation layout. An estimated 40 - 80% of new drug candidates are active but insoluble, and increasing their solubility or bioavailability has been a long-standing goal of the global pharmaceutical industry. Many drug excipient materials form solid dispersions with the drug active substance, leading to the development of an amorphous form of the drug with increased apparent solubility in water and increased dissolution rate. This is desirable for increasing the bioavailability of active pharmaceutical ingredients (「APIs」) that have low solubility but high permeability and are classified as Class II drugs in the Biopharmaceutics Classification System (「BCS」).

[0003] Various methods have been studied to improve the water solubility and poor dissolution rate of BCS Class II drugs, examples of which include the use of hydrotropes, complexation, solid dispersion, salt formation, emulsification, cocrystallization, and nanocrystal technology. Previous studies have shown that polyethylene glycol (PEG) itself is often not very effective in stabilizing the amorphous form of drugs and that PEG can produce brittle and hard crystalline formulations.

Summary of the Invention

[0004] The present invention contemplates a new type of carrier based on the formation of an interpolymer complex of PEG and polyacrylic acid (PAA), another FDA-approved excipient polymer / material, to enable higher apparent aqueous solubility and faster dissolution of BCS class II APIs.

[0005] Interpolymer complexes (or IPCs), which are generally known in the art, are products of non-covalent interactions between different macromolecules that are complementary in solution and in the solid state. These complexes include the following four generally recognized types: interpolyelectrolyte complexes (IPECs) or polyelectrolyte complexes (PECs), hydrogen-bonding interpolymer complexes, stereocomplexes, and charge-transfer complexes. Hydrogen-bonding interpolymer complexes are considered to be particularly relevant to the present invention. Interpolymer complexes can be prepared by mixing complementary polymers in solution or by matrix (template) polymerization. It is also possible to prepare IPCs at the liquid-liquid interface or on a solid or soft surface. Usually, the structure of the IPCs formed varies depending on many factors, such as the nature of the interacting polymers, the concentration of their solutions, the nature of the solvent, and the presence of inorganic ions or organic molecules in the solution.

[0006] The use of PEG+PAA-based IPCs as excipients for BCS class II drugs is defined by an improvement in the solubility of those drugs having an apparent solubility improvement of >100% compared to formulations of pure BCS class II APIs or PEG alone in pre-evaluations, as well as the ability to maintain supersaturation of the drug in aqueous solution for at least 30 minutes.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention includes a method for improving the water solubility of a drug substance classified in Class II of the Biopharmaceutics Classification System. This method includes mixing polyethylene glycol (PEG) with polyacrylic acid (PAA) in water under conditions sufficient to form at least some interpolymer complexes, and then adding the drug substance to this mixture.

[0008] Polyethylene glycol (PEG) preferably has a molecular weight of at least 1500 g / mol, 2000 g / mol, 2500 g / mol, and further 3000 g / mol. Polyethylene glycol preferably has a molecular weight of less than 10,000 g / mol, 9500 g / mol, 9000 g / mol, and further 8500 g / mol.

[0009] Polyacrylic acid (PAA) has a molecular weight of at least 800 g / mol, 1,000 g / mol, 1,250 g / mol, and further 1,500 g / mol. Polyacrylic acid preferably has a molecular weight of less than 4,000 g / mol, 3,500 g / mol, 3,000 g / mol, and further 2,500 g / mol.

[0010] Suitable conditions for forming at least some IPC between polyethylene glycol and polyacrylic acid are to mix PEG and PAA together with water. The ratio of PEG to PAA in such a mixture can be from 1:1 to 1:2. The total amount of polymer in such an aqueous solution can be from 0.25, 0.5, 0.75, or 1.0 wt% up to a maximum of 5, 4, 3, or 2 wt%, and about 1 wt% is generally preferred. Mixing is preferably carried out at room temperature for ease of the process, but other temperatures can also be used, and it will be readily understood that even slightly higher temperatures will result in more rapid formation of IPC. Then, the drug substance classified in Class II of the Biopharmaceutics Classification System is added to the resulting aqueous solution containing polyethylene glycol and polyacrylic acid, i.e., the resulting IPC. The API can be any Class II substance such as probucol or ketoprofen. Preferably, some kind of agitation such as mechanical stirring, shaking, suction, etc. is used to assist in dissolving the API in the solution.

[0011] Depending on the selected API, it may be beneficial to first dissolve the API in a solvent before the IPC aqueous solution or to dissolve it simultaneously with the IPC aqueous solution. For this purpose, water-soluble organic solvents such as alcohol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, etc. can be used. Alcohols, especially methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol are preferred solvents for this purpose. For example, a solution of the API in methanol at a concentration from 10 g / L, 15 g / L, or 20 g / L up to a maximum of 40 g / L, 34 g / L, or 30 g / L can be advantageously used.

[0012] The amount of API added to such an IPC aqueous solution depends in part on the specific API and the amount of polymer in the solution. The effectiveness of the method of the present invention can be determined by comparing the apparent increase in the solubility of the API in the aqueous solution and the ability to maintain a high saturation level for more than 30 minutes. The apparent solubility is the ratio of the solubility of the drug substance in the presence of the IPC-forming mixture to the solubility of the drug substance in water without any additives. Preferably, the apparent solubility increases by at least 100%, 200%, 250%, and even 300% even when measured after allowing the solution to stand for at least 30 minutes. The apparent solubility is preferably maintained at substantially the same level for at least 30 minutes and even 60 minutes. For the purposes of the present invention, the term "substantially the same level" means that the solubility remains within at least 10 percent of the original measured value.

Examples

[0013] To demonstrate the effectiveness of the present invention, a series of experiments can be conducted. The following materials are used. Polyacrylic acid (PAA) has a molecular weight of about 1800, and the polyethylene glycol used has a molecular weight of either 4000 or 8000 (as shown in Table I below). The API selected is either probucol (purity > 98%) or ketoprofen (purity > 98%). Each polymer or polymer combination shown in Table 1 is added to water in an amount to form a 1% polymer solution. A concentrated API solution in methanol is prepared by adding 0.2 grams of the drug to 10 mL of methanol (20 g / L of the drug in methanol).

[0014] For each example in Table 1, 912 μl of the indicated polymer solution is transferred to individual vials. Then, 48 μl of the drug solution in methanol is added to the polymer solution. These mixtures are stirred by aspiration and ejection in 3 cycles using an EVO 200 pipette.

[0015] Next, the samples were allowed to stand for 30 minutes. After 30 minutes, each sample was centrifuged at 13,600 rpm for 10 minutes. For HPLC analysis, a 30 μL aliquot was taken from the supernatant of each sample and diluted with 150 μL of methanol.

[0016] The concentration of the solubilized drug in each aliquot taken was determined by reverse phase high-performance liquid chromatography (HPLC) analysis. For this purpose, 2 μL of each diluted aliquot taken was injected into an Agilent 1100 HPLC system equipped with a reverse phase XDB-C8 column.

[0017] The drug concentration was determined from the elution profile measured using a linear calibration curve for each drug generated by identifying the least squares approximation of the line describing the relationship between the concentrations of four solutions of known concentrations (approximately 250, 500, 750, and 1000 mg / L) and the respective peak area integrals after injection of 2 μL of each drug in methanol. Each example was performed in triplicate and the results were averaged and reported in Table 1.

[0018] For comparison, the above-described test procedure was similarly performed by adding the drug to water in which no polymer was dissolved.

[0019]

Table 1

[0020] As shown in Table 1, by using the IPC provided in the present invention, the solubility of the API in the aqueous solution is greatly improved compared to pure water, PAA alone, and even PEG alone.

Claims

1. A method for improving the water solubility of an active pharmaceutical ingredient classified in Class II of the Biopharmaceutics Classification System, comprising: a. mixing polyethylene glycol with polyacrylic acid in water under conditions sufficient to allow the formation of at least some interpolymer complexes; b. adding the active pharmaceutical ingredient to the mixture.

2. The method according to claim 1, wherein the polyacrylic acid has a molecular weight in the range of 1000 to 3000.

3. The method according to claim 1, wherein the polyethylene glycol has a molecular weight in the range of 2000 to 10,000.

4. The method according to claim 1, wherein the polyethylene glycol and the polyacrylic acid are mixed before the addition of the active pharmaceutical ingredient.

5. The method according to claim 4, wherein the aqueous solution contains 0.5 to 2.5% by weight of the interpolymer complex.

6. The method according to claim 1, wherein the active pharmaceutical ingredient is added to a solvent before being added to the aqueous mixture of polyethylene glycol and polyacrylic acid.

7. The method according to claim 6, wherein the solvent is an alcohol having 1 to 4 carbon atoms.

8. The method according to claim 6, wherein the active pharmaceutical ingredient is added to the solvent in an amount of 1 gram per liter of solvent to 100 grams per liter of solvent.

9. The method according to claim 1, wherein the solubility of the active pharmaceutical ingredient in water with the interpolymer complex is improved by more than 200% compared to the solubility of the active ingredient in water alone.

10. The method according to claim 1, wherein the active pharmaceutical ingredient is probucol or ketoprofen. ​

Images