PHARMACEUTICAL MATRIX PELLETS, TABLETS AND COMPOSITION FOR THE PREPARATION THEREOF

Abstract: The present invention relates to pharmaceutical matrix pellet formulations providing an adequate drug release profile. The matrix of said pellets is formed from: (a) a hydrophilic compound selected among the group consisting of starch, a starch derivative and mixture thereof, and (b) a hydrophobic compound selected among the group consisting of wax, micro-crystalline wax and mixture thereof.

Description: Pharmaceutical matrix pellets, tablets and composition for the preparation thereof Abstract of the disclosure The present invention relates to pharma¬ ceutical matrix pellet formulations providing an adequate drug release profile. The matrix of said pellets is formed from : - (a) a hydrophilic compound selected from the group consisting of starch, a starch derivative and a mixture thereof, and - (b) a hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof. The prior art It is known to provide pellets with a coating, for example an outer polymer coating, for obtaining a specific drug release profile. The coating of pellets with a polymer layer is time consuming. Furthermore, many parameters (such as the layer thickness, the film quality, film aging, the processing parameters, microde- fects in the film, etc...) have an influence on the drug release rate. As the exact control of all these parameters is difficult, pellets have no precise drug release, but have a drug release rate varying within a certain range . Furthermore the preparation of the known coated (con¬ trolled release) pellets requires several production steps . So as to try to avoid this drawback, the man skilled in the art would suggest to use a thick polymer layer coating the pellets . The use of thick coating layer is however detrimental as it reduces the release rate. The aim of the present invention in to solve the problems due to the use of outer coating on pellets. The invention relates to matrix pellets not provided with any polymer coating, but having the desired release profile . Brief description of the invention The present invention relates to pharmaceutic¬ al matrix pellets in which solid particles containing a solid active agent or solid particles of an active agent, called hereafter in the present specification drug solid particles, are dispersed. In order to adapt the drug release profile the matrix consist of a mixture of a hydrophobic compound and a hydrophilic compound. The pharmaceutical matrix pellets of the invention contain : - (a) drug solid particles, - (b) a hydrophilic compound selected from the group consisting of starch, a starch derivative and a mixture thereof, and - (c) a hydrophobic compound selected among the group consisting of wax, microcrystalline wax and a mixture thereof, the said hydrophilic compound and the said hydrophobic compound being present in amounts and a ratio for ensuring an appropriate drug release. The hydrophilic compound is preferably a maltodextrines . These maltodextrines have preferably a DE (dextrose equivalent) value between 0 and 40, for example a value between 5 and 20. The hydrophobic waxes, microcrystalline waxes preferably have a melting point between 40°C and 90°C, most preferably between 50 and 80°C. Very convenient waxes are microcrystalline waxes with a melting point between 58°C (about 60°C) and 72°C (about 70°C) . The matrix pellets may further contain other additives, for example a compound selected from the group consisting of fatty acids, fats and mixtures thereof. The matrix pellets of the invention contain advantageously more than 20 % by weight of a mixture of the said hydrophilic and hydrophobic compounds. Preferably the matrix pellets of the invention contain more than 50 %, for example from 60 to 90, or even more, of a mixture of the said hydrophilic and hydrophobic compounds. According to practical examples of the matrix, the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and mixture thereof versus hydrophilic compound selected among the group consisting of starch, starch derivative and mixture thereof is between 1/10 and 10/1. Advantageously, said ratio is between 3/10 and 10/3, preferably between 1/4 and I/I. According to specific examples of pellets, the said ratio is higher than 0.6, preferably higher than 0.9, most preferably higher than 1, for example above 1.1 (1.14-1.2) . The matrix pellets may contain more than 15% by weight drug solid particles, preferably more than 25% by weight drug solid particles, most preferably more than 50% by weight drug solid particles. According to a further embodiment, the weight ratio of drug solid particles versus hydrophobic compound selected among the group consisting of wax, micro-crystalline wax and mixture thereof is higher than 0.3, advantageously higher than 0.5, preferably higher than 1 (for example between 1 and 5) . Matrix pellets with a weight ratio of hydrophobic/hydrophilic compound above 1 and with a weight ratio of active compound/hydrophobic compound above 1 allow a slow but nearly constant drug release. Matrix pellets of the invention have an exceptional stability for their release rate. This is especially the case when the ratio hydrophilic com¬ pound/hydrophobic compound is between 10/3 and 3/10, most preferably between 1/2 and 2/1. The invention relates to a composition for the preparation of matrix pellets of the invention. The composition contains : - (a) a hydrophilic compound selected from the group consisting of starch, a starch derivative and a mixture thereof, - (b) a hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof, and - (c) possibly other additives, in which the amount and ratio of (a) and (b) are as described above. Said composition, for example in the form of dry particles, is used as follows for the preparation of the pellets : heating of said hydrophobic compound at a temperature higher than its melting temperature, - mixing of said melted hydrophobic compound, said hydrophilic compound and the drug solid particles, and - cooling the mixture of hydrophobic compound, hydrophilic compound and drug solid particles at a temperature lower than the melting temperature of said hydrophobic compound so as to obtain matrix pellets with the said appropriate drug release. The composition has preferably the character¬ istics mentioned above for the matrix pellets of the invention, i.e. the hydrophilic compound, the hydrophobic compound, the weight ratio are preferably those mentioned above. The invention further relates to drug contain¬ ing dosage forms (such as tablets, pills, suppository, compressed dosage forms) containing matrix pellets of the invention as disclosed above, and to a process for the preparation of matrix pellets of the invention. The dosage forms of the invention contain a medicinally or pharmaceutically effective amount of drug. The process for the preparation of matrix pellets containing drug solid particles with an appropriate drug release comprises the following steps : - (a) heating a hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof at a temperature higher than its melting temperature (about the melting temperature or above) , - (b) mixing together said melted hydrophobic compound, a hydrophilic compound selected from the group consist- ing of starch, a starch derivative and a mixture thereof, and the drug solid particles, and (c) cooling the mixture hydrophobic compound, hydrophilic compound and drug solid particles to a temperature lower than the melting temperature of said hydrophobic compound so as to obtain matrix pellets with the said appropriate drug release. Advantageously, the process comprises a step of selecting and/or controlling the weight ratio between the said hydrophilic compound and the said hydrophobic compound for ensuring an appropriate drug release. Preferably, the process comprises a further step of selecting and/or controlling the weight ratio between the solid drug particles and the said hydrophobic compound. Other characteristics and details of the in¬ vention will be deducted from the following description and associated figures. Brief description of the drawings These figures show the release of a compound from matrix pellets consisting of : - figure 1 : * Waxy Maltodextrine as the hydrophilic compound, * 35 % (I) , 40 % (II) or 45 %(III) microcrystalline wax with a melting point of +. 60°C or 30 % (IV) microcrystalline wax with a melting point of +, 70°C as the hydrophobic com¬ pound, * the amount of active compound (ibuprofen) is 15 %. - figure 2 : * Potato Maltodextrine as the hydrophilic compound, * 35 % (V) , 40 % (VI) or 45 % (VII) microcrystalline wax with a melting point of +. 60°C or 35 % (VIII) microcrystalline wax with a melting point of + . 70°C, * the amount of active compound (ibuprofen) is 15 %. figure 3 : * Extruded waxy corn starch as hydrophilic compound, * 30 % IX) , 35 % (X) or 40 % (XI) microcrystalline wax with a melting point of ± 60°C as the hydrophobic compound, * the amount of active compound (ibuprofen) is 15 %. figure 4 : * Drum dried waxy corn starch as hydro- phillic compound, * 40 % (XII) or 45 % (XIII) microcrystalline wax with a melting point of ± 70°C or of 30 % (XIV) microcrystalline wax with a melting point of ± 70°C as hydrophobic compound, * the amount of active compound (ibuprofen) is 15 %. figure 5 : * Waxy Maltodextrine as hydrophilic compound, * microcrystalline wax with a melting point of +, 70°C as hydrophobic compound, * The amount of active compound (ibuprofen) is 15 % (XV) , 25% (XVI) , 50 % (XVII) , 60 % (XVIII) and 70 % (XIX) . figure 6 : * 50 % Extruded waxy corn starch as hydrophilic compound, * 35 % microcrystalline wax with a melting point of +, 60°C as the hydrophobic com¬ pound, * the amount of active compound (ibuprofen) is 15 %; the releases of the drug just after preparation (XX) and 20 months after preparation (XXI) being shown. figure 7 : * 50 % Potato Maltodextrine as the hydrophilic compound, * 35 % microcrystalline wax with a melting point of +, 60°C, * the amount of active compound (ibuprofen) is 15 %; the releases of the drug just after preparation (XXII) and 20 months after preparation (XXIII) being shown. Description of Examples In these examples ibuprofen has been used as the active compound. Ibuprofen had a particle size of +. 25 μm. The hydrophobic compounds used were : micro¬ crystalline waxes namely Lunacera ® P (Fuller GmbH, Germany) with a melting range between 58-62°C and Lunacera M ® with a melting range between 68-72°C. As hydrophilic compounds we have used : pregela- tinized starches (drum dried corn starch -drum dried waxy corn starch ) , extruded waxy corn starch and malto¬ dextrines with a DE value (Dextrose Equivalent) of 3 (Potato Maltodextrine) and of 10 (Waxy Maltodextrine) . The matrix was prepared as follows : the wax was molten by heating up to 65 °C in case of the Lunacera P and up to 75°C for the Lunacera M. Ibuprofen and a starch or a maltodextrine were mixed in a jacketed high shear granulator. During the mixing of ibuprofen and the starch or the maltodextrine, the molten wax was added. Ibuprofen, wax and starch or maltodextrine were mixed in order to obtain a homogeneous mass. Du¬ ring a slow and controlled cooling of the mass, under continuous stirring, matrix pellets were formed. The drug release from the matrix pellets was tested using the paddle method (USP XXII at a rotational speed of 100 rpm) . During the test, the pellets (amount equivalent with 45 mg ibuprofen) were fixed in a basket and put in a dissolution flask containing 900 mL phos¬ phate buffer (pH 7.2; 37 °C) . The ibuprofen release was measured. In the production method described hereabove, a high shear granulator is used. Other known methods and apparatuses (for example extrusion spheronisation) can be used for the production of matrix pellets. The following tables give an overview of the matrices produced and tested. Weight % Composi tion XV XVI XVII XVIII XIX Ibuprofen 15 6 70 Lunacera M 30 27 10 10 10 Lunacera P Waxy Maltodex¬ trine (DE=10) 55 40 32 2 12 Potato Malto¬ dextrine (Dl_=3) Starch DDWCS Starch t_WCS Weight ratio wax/starch or maltodextrine 0,55 0,55 0,55 0,02 1,5 Weight ratio drug/wax 0,5 2,0 3,3 3,0 The figures indicate that when modifying the wax content (see for example composition II and III) , the release from the matrixes can be adjusted. The release depends also on the type of wax used (see for example composition V and VII) . When examining the release profiles of compositions II, III,V,VI,VII, IX, X,XI, it appears that when increasing the ratio wax/starch the release rate is reduced. Fig. 5 shows that the matrix effect remains for pellets with a high drug loading. When examining the release profiles of the compositions XV,XVI and XVII, it appears that for a ratio wax/maltodextrine, the release rate will decrease with the drug content. Indeed, after 24 hours, about 75% of the 15% of ibuprofen is released (i.e. 0.75 x 15 = 11.25%) for the composition XV; after 24 hours, about 57% of the 25% of ibuprofen is released (i.e. 0.57 x 25 = 14.25%) for the composition XVI, and after 24 hours, about 45% of the 50% of ibuprofen is released (i.e. 0.45 x 50 = 22%) for the composition XV. It means that the presence of a higher drug content in some pellets will not greatly affect the release rate required. It means thus also that a different drug content in the pellets will not have a major influence on the drug release. Indeed, a difference of 10% of the drug content in the pellets (i.e. a drug content of 11% instead of 10%) will only increase the drug release after 24 hours of less than 1% (about less than 0.5%) , when having always the same ratio wax/maltodextrine or starch. The figures show that the pellets III having a weight ratio wax/starch or maltodextrine of 1.1 and pellets XIX with a weight ratio of 1.5 have a slow and nearly constant ibuprofen release. Such a slow and nearly constant drug release is also obtained for pellets XVI up to XIX with a weight ratio drug/wax above 1. Pellets having a nearly constant release rate can thus simply be produced by ensuring that the ratio drug/wax is above 1. The figures show also that when using a specific wax and a specific starch or maltodextrine, and when having a specific drug content in the pellets, an increase of the wax content will lead to a diminution of the release rate. Figures 6 and 7 show that the pellets of the invention have an exceptional stability. Indeed the difference between the release rate after 12 hours of pellets just prepared, and the release rate after 24 hours of pellets prepared 20 months ago is less than about 1%. This is a futher major advantage of matrix pellets of the invention with respect to pellets provided with a coating for the control of the release rate . The matrix pellets which can contain up to 80 % or even 90 % drug ( ibuprofen particles in the examples disclosed hereabove) can contain as drugs : antipyretic drugs; - analgesics; anti-anginosa (Verapamil, Nifidipine, Dilthiazem, ... ) ; antarrhytmics (disopyramide, quinidine, ...) ; antihypertensive drugs (/.-blocking agents, cloni- dine, ACE inhibitors, etc...) ; diuretics; antihypotensive drugs; drugs used in the treatment of cerebral vascular diseases (isoxsuprine, ...); - narcotic drugs; neuroleptics; anti-depressive drugs; anti-epileptics; hormones; - drugs used in the treatment of bronchospasm (theophylline, ... ) ; drugs used in the treatment of rhinitis and sinu¬ sitis; ibuprofen, and - mixtures thereof. The matrix pellets of the invention can be used for the preparation of tablets. For example, tablets can be prepared by compression of the matrix pellets of the examples I to XIX. The matrix pellets of the invention had also the property of masking on an effective way the taste of the drug particles.

Claims: What we clai is ; 1. Pharmaceutical matrix pellets containing : - (a) drug solid particles, - (b) a hydrophilic compound selected from the group consisting of starch, a starch derivative and mixture thereof, and - (c) a hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof, the said hydrophobic compound and the said hydrophilic compound being present in amounts for ensuring an appropriate drug release. 2. Matrix pellets according to claim 1, in which the hydrophilic compound is a maltodextrine with a DE value of 0 up to 40. 3. Matrix pellets according to claim 1, in which the matrix pellets further contain a compound selected from the group consisting of fatty acids, fats and mixtures thereof. 4. Matrix pellets according to claim 1, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 1/10 and 10/1. 5. Matrix pellets according to claim 1, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 3/10 and 10/3. 6. Matrix pellets according to claim 1, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 1/4 and 1/4. 7. Matrix pellets according to claim 4, in which the weight ratio of hydrophobic compound selected the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is higher than 0.6. 8. _ Matrix pellets according to claim 4, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is higher than 0.9. 9. Matrix pellets according to claim 4, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is higher than 1. 10. Matrix pellets according to claim 1, said matrix containing a medicinally effective amount of drug solid particles 11. Matrix pellets according to claim 1, said matrix containing more than 15% by weight drug solid particles . 12. Matrix pellets according to claim 1, said matrix containing more than 25% by weight drug solid particles . 13. Matrix pellets according to claim 1, said matrix containing more than 50% by weight drug solid particles. 14. Matrix pellets according to claim 1, in which the weight ratio drug solid particles versus hydrophobic compound selected from the group consisting of wax, microcrystalline wax and mixture thereof is higher than 0.3. 15. Matrix pellets according to claim 1, in which the weight ratio drug solid particles versus hydrophobic compound selected from the group consisting of wax, microcrystalline wax and mixture thereof is higher than 0.5. 16. Matrix pellets according to claim 1, in which the weight ratio drug solid particles versus hydrophobic compound selected from the group consisting of wax, microcrystalline wax and mixture thereof is higher than 1. 17. A composition for the preparation of matrix pellets containing drug solid particles with an appro¬ priate drug release, said composition containing - (a) a hydrophilic compound selected from the group consisting of starch, a starch derivative and a mixture thereof, and - (b) a hydrophobic compound selected among the group consisting of wax, micro-crystalline wax and a mixture thereof, said composition comprising said hydrophilic and hydrophobic compounds in a ratio for ensuring an appropriate drug release. 18. Composition of claim 17, in which the hydrophilic compound is a maltodextrine with a DE value of 0 up to 40. 19. Composition of claim 17, in which the composi¬ tion further contains a compound selected from the group consisting of fatty acids, fats and mixtures thereof. 20. Composition of claim 17, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 1/10 and 10/1. 21. Composition of claim 17, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is between 3/10 and 10/3. 22. Composition of claim 17, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 1/4 and l/_t. 23. Composition of claim 20, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is higher than 0.6. 24. Composition of claim 20, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is higher than 0.9. 25. Composition of claim 20, in which the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is higher than 1. 26. Drug containing dosage forms, said forms containing matrix pellets containing : - (a) a medicinally effective amount of a drug com¬ pound, - (b) a hydrophilic compound selected from the group consisting of starch, a starch derivative and a mixture thereof, and - (c) a hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof, the said hydrophobic and hydrophilic compounds being present in amounts and a ratio for ensuring an appropriate drug release. 27. Dosage forms of claim 26, in which the hydrophilic compound of the said matrix pellets is a maltodextrine with a DE value of 0 up to 40. 28. Dosage forms of claim 26, in which the said dosage forms further contains a compound selected from the group consisting of fatty acids, fats and mixtures thereof. 29. Dosage forms of claim 26, in which for the said dosage forms, the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and mixture thereof is between 1/10 and 10/1. 30. Dosage forms of claim 26, in which for the said dosage forms, the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is between 3/10 and 10/3. 31. Dosage forms of claim 26, in which for the said dosage for _ s, the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax ana a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is between 1/4 and 1/4. 32. Dosage forms of claim 29, in which for the said dosage forms, the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is higher than 0.6. 33. Dosage forms of claim 29, in which for the said dosage forms, the weight ratio of hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof versus hydrophilic compound selected among the group consisting of starch, starch derivative and a mixture thereof is higher than 0.9. 34. Dosage forms of claim 29, in which for the said dosage forms, the weight ratio of hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof versus hydrophilic compound selected from the group consisting of starch, starch derivative and a mixture thereof is higher than 1. 35. Dosage forms of claim 26, in which the said dosage forms contain more than 15% by weight drug com- pound. 36. Dosage forms of claim 26, in which the said dosage forms contain more than 25% by weight drug com¬ pound. 37. Dosage forms of claim 26, in which the said dosage forms contain more than 50% by weight drug com¬ pound. 38. Dosage forms of claim 26, in which for the said dosage forms, the weight ratio drug compound versus hydrophobic compound selected from the group consisting of wax, microcrystalline wax and a mixture thereof is higher is than 0.3. 39. Dosage forms of claim 26, in which for the said dosage forms, the weight ratio drug compound versus hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof is higher is than 0.5. 40. Dosage forms of claim 26, in which for the said dosage forms, the weight ratio drug compound versus hydrophobic compound selected from the group consisting of wax, micro-crystalline wax and a mixture thereof is higher is than 1. 41. Process for the preparation of matrix pellets containing drug solid particles with an appropriate drug release, said process comprising the following steps : - (a) heating of a hydrophobic compound selected among the group consisting of wax, microcrystalline wax and a mixture thereof at a temperature higher than its melting temperature, - (b) mixing together said melted hydrophobic compound, a hydrophilic compound selected from the group consist¬ ing of starch, a starch derivative and a mixture thereof, and the drug solid particles are mixed together, and (c) cooling the mixture of hydrophobic compound, hydrophilic compound and drug solid particles to a temperature lower than the melting temperature of said hydrophobic compound so as to obtain matrix pellets with the said appropriate drug release. 42. Process of claim 41 comprising a step of selecting the weight ratio between the said hydrophilic compound and the said hydrophobic compound for ensuring an appropriate drug release. 43. Process of claim 41 comprising a step of selecting the weight ratio between the solid drug particles and the said hydrophobic compound.

Inventors: REMON JEAN-PAUL, VERVAET CHRIS, REMON, JEAN-PAUL, VERVAET, CHRIS
Applicants: UNIV GENT, UNIVERSITEIT GENT
Application year: 1996
Main classification: A61K9
IPC codes: A61K9, A61K47