HK1061646B - Oral pharmaceutical composition containing a block copolymer - Google Patents

Description

Oral pharmaceutical composition containing block copolymer

The present invention relates to oral pharmaceutical compositions comprising a water-miscible micelle-forming block copolymer (hereinafter "copolymer") and a compound. The copolymer may be a diblock copolymer of formula AB or BA. The copolymer may also be a triblock copolymer of formula ABA or BAB. The copolymer may also be a multi-block copolymer having BA or AB repeating units of the formula A (BA) n or B (AB) n, where n is an integer and where A is selected from the group consisting of poly D-, L-, DL-lactic acid, poly D-, L-, DL-lactide, polyglycolic acid, polyglycolide, lactide-glycolate copolymers, poly epsilon-caprolactone and poly (3-hydroxybutyric acid); and B is selected from the group consisting of the hydrophilic polymers polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide and polyethylene glycol; alternatively, the hydrophilic polymer B itself may be a copolymer, for example a polyoxyethylene/polyoxypropylene block copolymer of the type known as Pluronics or Synperonics.

The above copolymer types are known, see for example US4,942,035, USA745,160, US4,526,938 or EP0,166,596, B1. These types of polymers are particularly useful in formulating pharmaceutical compositions for parenteral administration, since these copolymers allow the drug to be released over a prolonged period of time, such as several days. These polymers have not previously been considered suitable for oral administration because of the long release times of the drug, which make them unsuitable for achieving the desired oral drug absorption.

Surprisingly we have found that these polymers are in fact suitable for oral administration of compounds and are particularly suitable for formulating oral compositions producing compounds with low water solubility (less than 0.1mg/ml at the site of absorption). While not wishing to be bound by theory, it is believed that these copolymers act by a combination of enhanced solubility and prevention of precipitation, and thus are capable of greatly increasing the level of drug absorption after oral administration.

In particular, these polymers are particularly suitable for compounds which have a much lower solubility at the absorption site, typically the pH of the duodenum, ileum or colon, than in the stomach. These are generally basic compounds that dissolve more readily in the acidic stomach than at the slightly basic site of absorption.

A problem that may arise in absorption of compounds with low water solubility or basic compounds is that different patients and different dosages may lead to variations in the level of absorption.

One common factor that may affect drug absorption when administered orally is the pH change caused when the drug passes through the GI tract. Generally, when administered orally, the drug may be absorbed at any of the following sites: buccal, gastric, duodenal, ileal and colon. The pH may be different at each absorption site, with a distinct difference in pH in the stomach (pH1-3.5) and in the small intestine (pH 4-8). The solubility of the drug may vary with pH, resulting in the possibility of the drug coming out of solution as it passes through the GI tract. Particularly difficult is the dissolution of the drug and the decrease in solubility in the pH environment at the site of absorption.

This can lead to a reduction and variation in the rate of absorption for different doses and different patients. For example, we have found that the drug 1- (6-chloronaphthalen-2-ylsulfonyl) -4- [4- (4-pyridinyl) benzoyl ] piperazine (hereinafter compound 1), dissolves at acidic gastric pH but is not absorbed there, but the solubility decreases again at the major absorption sites duodenum, ileum and colon.

Compound 1 has factor Xa inhibitory activity, the enzyme coagulation factor also being a member of the thrombin cascade when its concentration is not inhibited or is inhibited to a reduced extent.

Compound 1 is disclosed in example 3 of WO 9957113.

Compound 1 is active in the treatment or prevention of a number of diseases, inter alia anticoagulant therapy, for example in the treatment or prevention of thrombotic diseases such as coronary artery and cerebrovascular disease. Further examples of such diseases include various cardiovascular and cerebrovascular diseases such as myocardial infarction, atherosclerosis, venous or arterial thrombosis, coagulation syndrome, vascular injury (including reocclusion and restenosis after angioplasty and coronary artery bypass surgery, thrombosis performed by vascular surgery or general surgery such as hip transplantation surgery, introduction of artificial heart valves or in recirculation of blood), cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischemia, and angina (including unstable angina).

For the reasons mentioned above, standard tablet formulations of compound 1 are not very satisfactory and have resulted in poor oral bioavailability and, most importantly, a large variation in absorption rates. The difference in absorption rates is important for any drug that affects the coagulation cascade, and it is noted that complete blocking of the coagulation cascade is an undesirable side effect. On the other hand low absorption levels of the compound will not cause any therapeutic effect.

Thus, good oral bioavailability, in particular low variability, is required.

We have found that the above polymers can be used as co-solvents and precipitation inhibitors, which polymers are also self-dispersing, water miscible and form micelles.

As a feature of the present invention we provide an oral pharmaceutical composition comprising a compound and a water-miscible micelle-forming block copolymer (hereinafter "copolymer"). Desirably the copolymer is a diblock copolymer of the formula AB or BA.

However, the copolymer may also be a triblock copolymer of the formula ABA or BAB. The copolymer may also be a multiblock copolymer having BA or AB repeat units of the formula A (BA) n or B (AB) n, where n is an integer (preferably the copolymer is a diblock copolymer of the formula AB or BA) and where A is selected from the group consisting of poly D-, L-, DL-lactic acid, poly D-, L-, DL-lactide, polyglycolic acid, polyglycolide, lactide-glycolate copolymer, poly epsilon-caprolactone and poly (3-hydroxybutyric acid); and B is selected from the group consisting of the hydrophilic polymers polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide and polyethylene glycol; alternatively, the hydrophilic polymer B itself may be a copolymer, for example a polyoxyethylene/polyoxypropylene block copolymer of the type known as Pluronics or Synperonics.

Another feature of the invention is the use of a water-miscible micelle-forming block copolymer to improve the oral bioavailability and/or variability of absorption of a compound. Desirably the copolymer is a diblock copolymer of the formula AB or BA. However, the copolymer may also be a triblock copolymer of the formula ABA or BAB. The copolymer may also be a multi-block copolymer having BA or AB repeating units of the formula A (BA) n or B (AB) n, wherein n is an integer (preferably the copolymer is a diblock copolymer of the formula AB or BA) and wherein A is selected from the group consisting of poly D-, L-, DL-lactic acid, poly D-, L-, DL-lactide, polyglycolic acid, polyglycolide, lactide-glycolate copolymer (PLGA), poly-epsilon-caprolactone and poly (3-hydroxybutyric acid); and B is selected from the group consisting of the hydrophilic polymers polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide and polyethylene glycol; alternatively, the hydrophilic polymer B itself may be a copolymer, for example a polyoxyethylene/polyoxypropylene block copolymer of the type known as Pluronics or Synperonics.

The compound is an organic molecule of MW < 800, which is formulated to work well with poorly water soluble compounds and with basic, compounds that are absorbed in the small intestine, and wherein the compound has a lower solubility at the site of absorption rather than at the pH in the stomach.

Preferably the copolymer is a diblock copolymer of formula AB or BA or a triblock copolymer of formula ABA or BAB. More preferably, the copolymer is a diblock copolymer of the formula AB or BA. Preferably, the A block portion of the block copolymer is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide). Preferably the Mw is between 500Da and 5000 Da. More preferably between 1000Da and 3000Da, and even more preferably between 1500Da and 2000Da. Preferably the B block portion of the copolymer is polyethylene glycol, preferably methoxy-polyethylene glycol. Preferably the Mw is between 500Da and 10,000Da, more preferably between 1,000Da and 5000 Da.

The most preferred copolymer is an AB diblock copolymer, wherein A is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide) and Mw is 2000Da, and B is methoxypolyethylene glycol and Mw is 2000Da.

The skilled person can determine that the polymer can form micelles by determining the critical micelle concentration (cmc). The micelle formation of this copolymer in an aqueous environment is supported by the determination of cmc and can be measured using the Wilhelmy plate method (S.A Hagan, A.G.ACoombes, M.C.Garnett, S.E, Dunn, M.C.Davies, L.Illum and S.S.Davis, Languir 1996, 12, 2153-.

The preparation of the polymers used is described in US4,942,035 and US4,526,938 or EP0,166,596, B1, zhu.k.j, lin.x.z and Yang s.l, preparation, characterization and properties of Polylactide (PLA) -poly (ethylene glycol) (PEG) copolymers, J appl.polym.sci., 39 (1990).

By the term "having a lower solubility at the absorption site than at the pH condition in the stomach", we mean that the solubility of the compound is at least 10 times, preferably 20 times, 30 times, 40 times, 50 times and 100 times higher at the pH condition in the stomach (pH1-2) than at the pH condition in the small intestine (pH 6-9).

By using the above polymers, we have found that the maximum supersaturation concentration of compound 1 is increased by a factor of 4-10 in vitro tests.

The preferred ratio of copolymer to compound is from 10: 1 to 0.25: 1, preferably from 5: 1 to 1: 1. One preferred compound is the compounds 1, 1- (5-chloroindol-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl ] piperazine (hereinafter referred to as compound 2) and 1- (5-chloroindol-2-ylsulfonyl) -4- [4- (1-imidazolyl) benzoyl ] piperazine (hereinafter referred to as compound 3).

Compound 2 and compound 3 are disclosed in examples 3 and 6, respectively, of WO 9957113. Compounds 2 and 3 are factor Xa inhibitors as compound 1.

The composition may contain 0.01mg to 1g of the compound. Additional excipients may be included in the composition.

Generally the compound will be present in an amount of from 1 to 80%, preferably from 1 to 50% (especially from 2 to 15% or from 2 to 20%) by weight of the composition.

The composition may be prepared by mixing the compound and the polymer, preferably cryogenically grinding the polymer, then mixing with the compound, and then compression may be employed. The preferred method of preparing the composition is as a solid dispersion, a technique which is well known in the art and generally comprises the steps of: the compound and the polymer are dissolved in a conventional solvent, and then the solvent is evaporated. Methods of evaporating the solvent include rotary evaporation, spray drying with appropriate excipients, freeze drying and thin film evaporation. Other techniques such as solvent-controlled precipitation, pH-controlled precipitation, supercritical fluid techniques and heated melt extrusion may be employed. For assistance purposes, the melt in the process may be extruded with any necessary excipients, such as plasticizers, including supercritical fluids. The melt can be extruded directly or filled into capsules using a heated melt extrusion process.

In referring to solid dispersions, we do not exclude the possibility that a portion of the compound may be dissolved in the polymer used, and the extracted portion, if present, will depend on the physical properties of the compound and polymer selected.

Conventional excipients that may be added include preservatives, stabilizers, antioxidants, silica flow modifiers, antiadherents or glidants.

The invention will now be described by way of the following non-limiting examples.

Preparation of solid dispersions

The ratio is 1: 5.

0.5g of drug (Compound 1) and 2.5g of polymer were weighed out and added directly to a 250ml round bottom flask and dissolved in 63ml methanol/dichloromethane (50: 50). The solvent was removed in a rotary evaporator. The formulation was dried in a vacuum oven at 40 ℃ under high vacuum for 48 hours.

Other proportions by weight and volume refer to the above formulations.

Solubility measurement

Solubility Compound 1

Water < 5ug/ml

pH1.2 250ug/ml

pH6.8 2ug/ml

In vitro dissolution of solid dispersions

Dissolution method by pH change

The formulation was weighed and added to a hard gelatin capsule (equivalent to 25mg drug) and dissolved in 500ml 0.1N HCl at 37 ℃ for 1 hour (stirring speed 100 rpm). 5ml samples were taken at 55 minutes and the media replaced. 10ml 2.5M KH after 1 hour₂PO₄A/16.72% (w/v) NaOH solution was added to the HCl to adjust the pH to 6.5. Subsequently 5ml samples were taken at 5, 15, 30, 45 and 60 minutes with a plastic syringe and the medium was replaced after each sampling time point. Each timeThe samples were centrifuged (14,000rpm) for 15 minutes at ambient temperature and subsequently analyzed by HPLC using the following conditions:

eluent: 40% ACN/60% Water/0.2% TFA

Column: 25cm HIRPB, 4.6mm internal diameter

And (3) testing wavelength: 236nm

Flow rate: 1.5ml/min

Temperature: at normal temperature

Injection volume: 80 μ l

Retention time: about 6 minutes

pH6.5 dissolution method

The formulation was weighed out and added to hard gelatin capsules (equivalent to 25mg drug) and dissolved at 37 ℃ in a solution containing 500ml of 0.1N HCl and 10ml of 2.5M KH₂PO₄16.72% (w/v) NaOH solution in a medium for 1 hour (stirring speed 100 rpm). Subsequently 5ml samples were taken at 5, 15, 30, 45 and 60 minutes with a plastic syringe and the medium was replaced after each sampling time point. Each sample was centrifuged (14,000rpm) at room temperature for 15 minutes and then analyzed by HPLC using the same conditions as the pH change method.

FIG. 1 shows the release profile of solid dispersions of Compound 1 and PLA PEG AB block copolymer and Pluronic polymers using a pH change dissolution method. A conventional suspension of compound 1 was used as a control. The figure shows that PLA-PEG polymers are the best solid dispersion matrix material because the highest degree of supersaturation is achieved with this polymer. The solid dispersions prepared with Pluronic F-68 and F-127 did not provide any significant advantage over the conventional suspension of Compound 1. Similar to conventional suspensions, Pluronic formulations do not maintain supersaturation levels at higher pH.

FIG. 2 shows the release profile of two PLA PEG AB block copolymer formulations of Compound 1 in the dissolution test at pH6.5 (SD is the solid dispersion and mix is the blend). A conventional suspension of compound 1 was used as a control. The figure shows that PLA: PEG polymers can increase the dissolution (mixture) of compound 1 in the absence of any of the aforementioned formulations. This may be the result of the polymer solubilizing the compound.

Figure 3 shows the release profile of two PLA: PEG AB block copolymer formulations of compound 1 in a pH change dissolution test (SD is solid dispersion, mix is mixture). A conventional suspension of compound 1 was used as a control. The graph shows that the PLA: PEG polymer is able to maintain the degree of supersaturation of compound 1 in both the formulated and unformulated state (i.e., SD or mixture). Fig. 2 and 3 show that PLA: PEG can function by a combination of enhancing solubility and preventing precipitation.

Claims (33)

1. An oral pharmaceutical composition comprising a compound and a self-dispersing, water-miscible micelle-forming diblock copolymer of the general formula AB or BA, wherein A is selected from the group consisting of poly D-, L-, DL-lactic acid, poly D-, L-, DL-lactide, polyglycolic acid, polyglycolide, lactide-glycolate copolymer, poly-epsilon-caprolactone and poly (3-hydroxybutyric acid); and B is selected from the group consisting of the hydrophilic polymers polyvinyl alcohol, polyethylene oxide and polyethylene glycol; or the hydrophilic polymer B itself may be a copolymer,

wherein the compound has a significantly lower solubility at the pH at the absorption site than in the stomach.

2. An oral pharmaceutical composition according to claim 1, wherein the hydrophilic polymer B is a polyoxyethylene/polyoxypropylene block copolymer of the type known as Pluronics or Synperonics.

3. The oral pharmaceutical composition of claim 1, wherein the a block portion of the copolymer is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide).

4. The oral pharmaceutical composition of claim 3, wherein the Mw of the A polymer is between 500Da and 5,000 Da.

5. An oral pharmaceutical composition according to claim 4, wherein the Mw of the A polymer is between 1000Da and 3000 Da.

6. An oral pharmaceutical composition according to claim 5, wherein the Mw of the A polymer is between 1300Da and 2200 Da.

7. The oral pharmaceutical composition of claim 6, wherein the Mw of the A polymer is 2000Da.

8. The oral pharmaceutical composition of any one of claims 1-7, wherein the B block portion of the copolymer is polyethylene glycol.

9. The oral pharmaceutical composition of claim 8 wherein the B block portion of the copolymer is methoxy-polyethylene glycol.

10. The oral pharmaceutical composition of claim 8, wherein the Mw of the B polymer is between 500Da and 10,000 Da.

11. The oral pharmaceutical composition of claim 10, wherein the Mw of the B polymer is between 1,000Da and 5000 Da.

12. An oral pharmaceutical composition according to any one of claims 1 to 7 comprising a compound and a self-dispersing, water-miscible, micelle-forming diblock copolymer of the general formula AB or BA, wherein A is poly-L-lactide of Mw 2000Da, B is polyethylene glycol of Mw 2000Da, and

the compound is significantly less soluble at the pH conditions at the site of absorption than in the stomach.

13. An oral pharmaceutical composition according to any one of claims 1 to 7 comprising a compound and a self-dispersing, water-miscible micelle-forming diblock copolymer of the general formula AB or BA, wherein A is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide), Mw is 2000Da, B is methoxypolyethylene glycol, Mw is 2000Da, and

the compound is significantly less soluble at the pH conditions at the site of absorption than in the stomach.

14. The oral pharmaceutical composition of any one of claims 1-7, wherein the compound is selected from the group consisting of 1- (6-chloronaphthalen-2-ylsulfonyl) -4- [4- (4-pyridinyl) benzoyl ] piperazine, 1- (5-chloroindol-2-ylsulfonyl) -4- [4- (4-pyridinyl) benzoyl ] piperazine and 1- (5-chloroindol-2-ylsulfonyl) -4- [4- (1-imidazolyl) benzoyl ] piperazine.

15. The oral pharmaceutical composition of any one of claims 1-7, wherein the composition comprises 0.01mg-1g of the compound.

16. The oral pharmaceutical composition of any one of claims 1-7, wherein the compound is basic.

17. The oral pharmaceutical composition of any one of claims 1-7, wherein said compound is an organic molecule with MW < 800.

18. The oral pharmaceutical composition of any one of claims 1-7, wherein said composition is a solid dispersion obtained by the steps of: mixing the compound with the copolymer; dissolving the compound and the polymer in a conventional solvent and then evaporating the solvent; controlling precipitation by a solvent; controlling the pH value for precipitation; supercritical fluid technology or heating melt extrusion.

19. An oral pharmaceutical composition according to claim 1, which comprises a compound and a self-dispersing, water-miscible and micelle-forming diblock copolymer of the general formula AB or BA, wherein the a block part of the copolymer is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide) and the Mw of polymer a is between 500Da and 5,000 Da;

the B block portion of the copolymer is polyethylene glycol and the Mw of polymer B is between 500Da and 10,000 Da;

wherein the compound has a significantly lower solubility at the pH at the absorption site than in the stomach.

20. The oral pharmaceutical composition of claim 19, wherein the Mw of polymer a is between 1000Da and 3,000Da and the Mw of polymer B is between 1000Da and 5,000 Da.

21. The oral pharmaceutical composition of claim 19 or 20, wherein polymer B is methoxy-polyethylene glycol.

22. The oral pharmaceutical composition of claim 19 or 20, wherein said compound is an organic molecule with MW < 800.

23. Use of a water-miscible, micelle-forming diblock copolymer of the general formula AB or BA and a compound wherein a is selected from the group consisting of poly D-, L-, DL-lactic acid, poly D-, L-, DL-lactide, polyglycolic acid, polyglycolide, lactide-glycolate copolymer, poly-e-caprolactone and poly (3-hydroxybutyric acid) for the preparation of a pharmaceutical composition; and B is selected from the group consisting of the hydrophilic polymers polyvinyl alcohol, polyethylene oxide and polyethylene glycol; or the hydrophilic polymer B may itself be a copolymer, said composition being intended to improve the oral bioavailability and/or the variability of the absorption rate of the compound.

24. Use according to claim 23, wherein the hydrophilic polymer B is a polyoxyethylene/polyoxypropylene block copolymer of the type known as Pluronics or Synperonics.

25. The use of claim 23, wherein the a block portion of the copolymer is poly- (D-, L-or DL-lactic acid) or poly (D-, L-or DL-lactide).

26. The use of claim 25, wherein the Mw of the a polymer is between 500Da and 5,000 Da.

27. Use according to claim 26, wherein the Mw of the a polymer is between 1000Da and 3000 Da.

28. Use according to claim 27, wherein the Mw of the a polymer is between 1300Da and 2200 Da.

29. The use of claim 28 wherein the Mw of the a polymer is 2000Da.

30. The use of any one of claims 25 to 29, wherein the B block portion of the copolymer is polyethylene glycol.

31. The use of claim 30, wherein the B block portion of the copolymer is methoxy-polyethylene glycol.

32. The use of claim 30 wherein the Mw of the B polymer is between 500Da and 10,000 Da.

33. The use of claim 32 wherein the Mw of the B polymer is between 1,000Da and 5000 Da.