Formulations For Poorly Soluble Drugs

Abstract

The present invention provides a drug delivery system comprising nanoparticles or microparticles of a water poorly soluble drug dispersed in a polymeric bead containing essentially only of hydrophilic polymers (i.e. without hydrophobic polymers). The present invention further provides a method of producing the drug delivery system of the invention.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carried out in practice, some preferred embodiments will now be described, by way of non-limiting examples only, with reference to the accompanying drawings, in which:

FIG. 1A shows an electron microscope picture of a polymeric bead containing nanoparticles of simvastatine, prepared as described in Example 1 which are vacuum dried;

FIG. 1B shows an electron microscope picture of a cross section of the polymeric bead shown in FIG. 1A.

FIG. 1C shows an electron microscope picture of a polymeric bead containing nanoparticles of simvastatine, prepared as described in Example 1 which are air dried.

FIG. 1D shows an electron microscope picture of a cross section of the polymeric bead shown in. FIG. 1C.

FIG. 2 shows the dissolution of two samples of beads of the invention containing simvastatine as compared to dissolution of commercial simvastatine.

FIG. 3 shows an electron microscope picture of simvastatine crystals after solvent evaporation carried out without using bead formation.

FIG. 4 shows electron microscope pictures of simvastatine nanoparticles after solvent evaporation from bead nanoemulsion systems.

FIG. 5 shows the effect of varying concentrations of phosphate buffer (pH˜6.8) on beads disintegration.

FIG. 6 shows the effect of varying concentrations of citrate buffer (pH˜6.8) on beads disintegration.

FIG. 7 shows the effect of various crosslinking ions at a concentration of 25 mM on beads disintegration.

FIG. 8 shows the effect of various crosslinking ions at a concentration of 100 mM on beads disintegration.

DETAILED DESCRIPTION OF THE INVENTION

Tailoring of the Polymeric Bead Parameters:

The following parameters may be varied when designing the drug delivery system of the present invention:

• • 1) Droplets size in the nano/microemulsion may be tailored by controlling volatile solvent type, co-solvent type, surfactants and co-surfactant concentration and type, by controlling the cycles in high-pressure homogenizer (in case high pressure homogenization is utilized to obtain the nanoemulsions), o/w ratio and temperature.
  • 2) Type and molecular weight of the polysaccharide, (e.g. Alginate, K-Carrageenan, Chitosan, Gellan gum, Agarose, Pectin etc,) or synthetic polymers.
  • 3) Structure of alginates (e.g. different ratio of guluronic and mannuronic acids).
  • 4) Type and concentration of the crosslinking agent (also termed “gelling agent”) ion solution (cation: Ca⁺², Ba⁺², AL⁺², Fe⁺², Cu⁺², poly(amino acids) etc., and non-crosslinking ion (and Na⁺).
  • 5) Crosslinking duration.
  • 6) Matrix composition of material other than the bead forming polymer: other materials may be added, such as Silica, HPMC, Lactose, sodium chloride etc., which affect the morphology, porosity, size, and shrinkage of beads upon drying, disintegration rate and hydrophobicity.
  • 7) The size of the polysaccharide beads can be controlled by controlling nozzle size, frequency, amplitude, velocity, physical parameters.
  • 8) The rate of disintegration may be controlled by adding a disintegrate such as EDTA, phosphate or citrate ions, and controlling the amount of the disintegrant.

EXAMPLE 1

Solutions Preparation:

4% Alginate Solution:

16 g of Alginic acid sodium salt (Sigma, low viscosity, 2% solution-250 cps) was dissolved in 400 g distilled water (4% w/w), together with 0.4 g of Bronopol (preserving material). The mixture was mixed on magnetic stirrer for about 48 hours and heated to about 37° C. until complete dissolution.

100 mM CaCl₂ Solution (Crosslinking Agent)

14.8 g of Dihydrate Calcium Chloride (Merck) was dissolved in 1000 g distilled water.

1. Emulsification

Oil in water emulsion 20% oil phase fraction, 80% aqueous phase fraction was prepared, containing 3% w/w total surfactant (mixture of Tween 20, commercial name of ethoxylated sorbitan mono-laurate and Span 20, commercial name of sorbitan monolaurate HLB=10) concentration.

3.3584 g of Simvastatine powder (Teva Pharmaceuticals, Israel) used as the poorly soluble drug was weighed and mixed with 80.0 g toluene until complete dissolution of the drug is achieved. Final concentration of Simvastatine is 42 mg/g toluene.

1.02 g Tween 20 was weighed and dissolved in 160.26 g distilled water saturated with toluene (filtered through 0.2 μm filter) .

4.97 g Span 20 was weighed and mixed with the 40.23 g solution of 42 mg/g Simvastatine in toluene, and stirred about 10 min together. The organic phase was added carefully to the water phase and mixed for 5 min in an Ultra Turrax homogenizer at 8000 RPM. A coarse, homogeneous emulsion was obtained. This emulsion was introduced into a high pressure homogenizer (Stansted), and was circulated through the high-pressure-homogenizer twice at 17,000 psi.

Z-average particles size of the resulting emulsion was 250-255 nm.

2. Beads Formation:

95.1 g of sodium alginate solution (4% w/w) and 3.8 g of Silica 60 Å Frutarom) used to prevent shrinking upon drying, were mixed together for about 10 min by a magnetic stirrer until the silica was dispersed homogeneously in the alginate solution. Then 95.1 g of the above o/w emulsion were added and stirred together until homogenous mixture was achieved. The alginate-emulsion mixture was introduced into an Innotech encapsulator, and jetted into 100 mM CaCl₂ crosslinking solution.

The Innotech encapsulator allows tailoring the final size of the beads by selecting the proper instrument parameters. In this example, the parameters were:

Nozzle size—300 μm.

Voltage—0.914 Kv.

Amplitude—3.

Frequency—1550 Hz.

Pressure—0.4 bar.

The beads were kept in the crosslinking solution for 30 min.

Then, the beads were rinsed with about 2 liters of distilled water, filtered and air dried in an oven, at temperature of about 35° C. for 48 hours, in order to remove the water and the volatile solvent.

The final result was dry beads in the size range of less than 1 mm in which nanoparticles of Simvastatine were dispersed, as verified by electron microscopy and shown in FIG. 1. FIG. 1A shows an electron microscope picture of a polymeric bead containing nanoparticles of simvastatine, which was vacuum dried. A cross section of same bead is shown in FIG. 1B. FIG. 1C shows an electron microscope picture of a polymeric bead containing nanoparticles of simvastatine, which was air dried. A cross section of same bead is shown in FIG. 1D.

EXAMPLE 2

Reduction of Gelling Time and Gelling Ion Concentration

Solutions Preparations:

4% Alginate Solution: Was Prepared as Described in Example 1.

25 mM CaCl₂ Solution (Crosslinking Agent)

3.7 g of Dihydrate Calcium Chloride (Merck) was dissolved in 1000 g distilled water.

1. Emulsification

Oil in water emulsion 20% oil phase fraction, 80% aqeous phase fraction was prepared, containing 3% w/w total surfactant (mixture of Tween 20 and Span 20, HLB=10) concentration. 3.7869 g of Simvastatine powder (Teva Pharmaceuticals, Israel) used as the poorly soluble drug was weighed and mixed with 90.1 g toluene until complete dissolution of the drug is achieved. Final concentration of Simvastatine is 42 mg/g toluene.

1.04 g Tween 20 was weighed and dissolved in 160.54 g distilled water saturated with toluene (filtered through 0.2 μm filter) .

4.97 g span 20 was weighed and mixed with the 40.55 g solution of 42 mg/g Simvastatine in toluene, and stirred about 10 min together. The organic phase was added carefully to the water phase and mixed for 5 min in an Ultra Turrax homogenizer at 8000 RPM. A coarse, homogeneous emulsion was obtained. This emulsion was introduced into a high pressure homogenizer (Stansted), and was circulated through the high-pressure-homogenizer twice at 17,000 psi.

Z-average particles size of the resulting emulsion was 194-21 nm.

2. Beads Formation:

75.3 g of sodium alginate solution (4% w/w) and 3.0 g of silica 60 Å (Frutarom) were mixed together for about 10 min by a magnetic stirrer until the silica was dispersed homogeneously in the alginate solution. Then 75.2 g of the above o/w emulsion were added and stirred together until homogenous mixture was achieved. The alginate-emulsion mixture was introduced into an Innotech encapsulator, and jetted into 25 mM CaCl₂ crosslinking solution.

The Innotech encapsulator allows tailoring the final size of the beads by selecting the proper instrument parameters. In this example, the parameters were:

Nozzle size—300 μm.

Voltage—1.005 Kv.

Amplitude—3.

Frequency—1527 Hz.

Pressure˜0.3 bar.

The beads were kept in the crosslinking solution for 10 min.

Then, the beads were rinsed with about 2 liters of distilled water, filtered and air dried in an oven, at temperature of about 35° C. for 48 hours, in order to remove the water and the volatile solvent.

EXAMPLE 3

Alteration of Surfactant

Solutions Preparations:

4% Alginate Solution:

Was prepared as described in Example 1.

25 mM CaCl₂ Solution (Crosslinking Agent)

Was prepared as described in Example 2.

1. Emulsification

Oil in water emulsion 20% oil phase fraction, 80% aqeous phase fraction was prepared, containing 3% (w/w) total surfactant (Hexaglycerol sesquistearate, SY-GLYSTER SS-5S, SAKAMOTO YAKUHIN KOGYO CO., LTD. HLB=9.9) concentration. 3.7807 g of Simvastatine powder (Teva Pharmaceuticals, Israel), used as the poorly soluble drug was weighed and mixed with 90.1 g toluene until complete dissolution of the drug is achieved. Final concentration of Simvastatine is 42 mg/g toluene .

4.02 g Hexaglycerol sesquistearate was weighed and dissolved in 160.28 g distilled water saturated with toluene (filtered through 0.2 μm filter).

2.02 g Hexaglycerol sesquistearate was weighed and mixed with the 40.46 g solution of 42 mg/g Simvastatine in toluene, and stirred about 10 min together. The organic phase was added carefully to the water phase and mixed for 5 min in an Ultra Turrax homogenizer at 8000 RPM. A coarse, homogeneous emulsion was obtained. This emulsion was introduced into a high-pressure homogenizer (Stansted), and was circulated through the high-pressure-homogenizer twice at 17,000 psi.

Z-average particles size of the resulting emulsion was 126-140 nm.

2. Beads formation:

75.2 g of sodium alginate solution (4% w/w) and 3.0 g of Silica 60 Å (Frutarom) were mixed together for about 10 min by a magnetic stirrer until the silica was dispersed homogeneously in the alginate solution. Then 75.5 g of the above o/w emulsion were added and stirred together until homogenous mixture was achieved. The alginate-emulsion mixture was introduced into an Innotech encapsulator, and jetted into 25 mM CaCl₂ crosslinking solution.

The Innotech encapsulator allows tailoring the final size of the beads by selecting the proper instrument parameters. In this example, the parameters were:

Nozzle size—300 μm.

Voltage—1.005 Kv.

Amplitude—3.

Frequency—1527 Hz.

Pressure˜0.3 bar.

The beads were kept in the crosslinking solution for 10 min.

Then, the beads were rinsed with about 2 liters of distilled water, filtered and air dried in an oven, at temperature of about 35° C. for 48 hours, in order to remove the water and the volatile solvent.

Dissolution Tests

Dissolution test was performed to the dried beads and the results are shown in FIG. 2, where samples 2 and 3 are the beads of the invention compared to commercial simvastatine.

Dissolution test parameters:

Instrument: Caleva 7ST, Test method: USP II at 75 rpm

Dissolution medium: Citarate Buffer 0.1M pH˜6.8

Assay Procedure: UV at 239 nm.

Dissolution test shows (see FIG. 2) the advantage of the beads of the invention, which uses hydrophilic polymer beads containing dispersed nano-particles of simvastatine (water insoluble drug) by solvent evaporation upon commercial simvastatine particles.

The overall dissolution rate of the beads containing dispersed nanoparticles is much faster than that of commercial drug particles. Using beads nanoparticles system enable tailoring of release kinetics.

The dried resulting beads can be inserted to capsules or compressed to tablets.

EXAMPLE 4

Solvent Evaporation of Nanoemulsion in Conventional Way

In this example solvent evaporation was performed to the nanoemulsion before beads formation. This experiment prove the necessity of solvent evaporation after the beads formation in order to prevent crystal formation and growing of the lipophilic drug.

1. Emulsification

Oil in water emulsion 20% oil phase fraction, 80% aqueous phase fraction was prepared, containing 3% (w/w) total surfactant (mixture of Tween 20 and Span 20, HLB=10) concentration. 2.5231 g of Simvastatine powder (Teva Pharmaceuticals, Israel) used as the poorly soluble drug was weighed and mixed with 61.7 g toluene until complete dissolution of the drug is achieved. Final concentration of Simvastatine is 41 mg/g toluene.

0.51 g Tween 20 was weighed and dissolved in 80.26 g distilled water saturated with toluene (filtered through 0.2 μm filter).

2.49 g Span 20 was weighed and mixed with the 20.56 g solution of 41 mg/g Simvastatine in toluene, and stirred about 10 min together. The organic phase was added carefully to the water phase and mixed for 5 min in an Ultra Turrax homogenizer at 8000 RPM. A coarse, homogeneous emulsion was obtained. This emulsion was introduced into a high pressure homogenizer, (Stansted), and was circulated through the high-pressure-homogenizer twice at 17,000 psi.

Z-average particles size of the resulting emulsion was 186-198 nm.

The organic solvent (toluene) was evaporated with Rotavapor (R-114 BUCHI) from the emulsion to form a dispersion of lipophilic drug in water. The organic solvent evaporation was performed in four steps, water was added up to the initial weight after each step.

After several hours, it was found that huge large crystals (needles) (crystal size: 0.5-2 mm) of the raw material were formed (see FIG. 3) that indicate the instability of the drug nanoparticles that was formed after evaporation, while the evaporation is performed not within the polymeric bead.

Against this, when the solvent evaporation was performed after the beads formation, the simvastatine remain as nanoparticles while performing the evaporation without beads forms large crystals of simvastatine (see FIG. 4). These experiments prove the necessity of solvent evaporation after the beads formation in order to prevent forming and growing of the drug crystals, which significantly reduce the bioavailability of the poorly soluble drug.

EXAMPLE 5

Disintegrant Effect on the Beads

Alginate beads are insoluble in water or acidic media. In order to enable the disintegration of the drug uptake, a disintegrant was included in the drug formulation, which contains the beads. The effect of disintegrant is demonstrated by experiments in which the beads were immersed in liquid containing the disintegrant.

The beads disintegration measurements were performed using turbidimeter (HACH RATIO/XR). The turbidity values represent the beads disintegration. It is expected that the disintegration will enhance the drug release in the system. It should be emphasize that the beads cannot disintegrate without the presence of suitable disintegrating agents.

FIG. 5 demonstrates the influence of phosphate buffer concentrations, in the range of 0.05M-0.25M, on the beads disintegration rate. In 0.05M phosphate buffer the beads were slightly disintegrated while in 0.25M phosphate buffer the beads were completely disintegrated within 10 mins.

FIG. 6 demonstrates the influence of citrate buffer concentrations, in the range of 0.05M-0.25M, on the beads disintegration rate. The beads were completely disintegrated within 10 mins in all tested concentrations (0.05M-0.25M) of citrate buffer. The citrate buffer is more efficient disintegrating agent than phosphate buffer and it disintegrate the beads in lower concentration.

In addition to the examination of disintegrating agents (which is in the external phase) on the beads disintegration, the influence of various crosslinking ions (Ca⁺², Ba⁺², Fe⁺³, Zn⁺² and Co⁺²) in two different concentrations (which are added in the bead formation process) on the beads disintegration was determined.

FIGS. 7 and 8 demonstrate the influence of different crosslinking cation on the beads disintegration.

It was found that the beads disintegration depends on the crosslinking ion according to the following order: Ca⁺²>Zn⁺²>Fe⁺³>Co⁺²>Ba⁺². The obtained order is influenced by several parameters such as: the cation valence, the cationic radius, and the ability of the disintegrating agent to competitive on the cation against the alginate polymer.

It was found that by proper selection of disintegrants (type and concentration) and crosslinking (type and concentration) we can control the release rate of the drug.

EXAMPLE 6

Microemulsions

Microemulsions were prepared by mixing, without any special equipment—of the solvent (which contains the pre-dissolved drug molecule), the surfactant, co-surfactant and water, at proper composition according to the phase diagram. Than, the obtained microemulsion was mixed with alginate solutions, which upon contact with 2% CaCl₂ solution formed beads in which the microemulsion droplets were dispersed within. The last stage was drying the beads, which lead to formation of drug nanoparticles (size 10-50 nm) dispersed within the bead.

Beads formation: 2.5% Alginate (type LF10/60) solution was mixed with 25% of microemulsion having the composition:

9.1% Brij 96V (polyoxyethylene 10 oleyl ether surfactant)

81.8% Ethanol/Water 1:1

9.1% Limonene/Triglyme 1:1 which contains the dissolved drug.

In an alternative procedure: 2.5% Alginate (type LF 10/60) solution was mixed with 25% microemulsion having the composition:

8% SDS (dodecyl sodium sulfate surfactant)

82% Water

10% BuAc/2-Propanol 1:1 containing the dissolved drug.

Claims

1-40. (canceled)

41. A drug delivery system comprising nanoparticles or microparticles of a poorly soluble drug dispersed in a polymeric hydrophilic bead and a disintegrate mixed with the bead.

42. A drug according to claim 41, wherein the polymeric bead consists essentially of a single species of hydrophilic polymer.

43. A drug delivery system according to claim 42, wherein the polymeric bead is selected from: a polysaccharide polymer, a synthetic polymer, and a protein.

44. A drug delivery system according to claim 41, wherein the poorly soluble drug is selected from: simvastatine, statines, risperidone, carvedilol, carbamazepine, oxcarbazepine, zaleplon, galantamine, anti Alzheimer, anti epileptic, anti parkinsonian, and other used for CNS indications.

45. A drug delivery system according to claim 41, wherein the nanoparticles are in an amorphous, non crystalline state which enhances dissolution of the drug.

46. A drug delivery system according to claim 41, further comprising a crosslinker.

47. A drug delivery system according to claim 41, wherein the crosslinker is a multivalent cation.

48. A drug delivery system according to claim 41, wherein the disintegrate is capable of breaking the crosslinking by replacing or chelation of the crosslinking multivalent cation.

49. A drug delivery system according to claim 41, wherein the disintegrate is a calcium chelator.

50. A drug delivery system according to claim 41 wherein the beads are gelatin beads.

51. A drug delivery system comprising an active ingredient dispersed within a crosslinked polymeric bead wherein the crosslinking is by a cation selected from calcium, iron, magnesium and copper and wherein the drug delivery system further comprises as a disintegrant a chelator of calcium.

52. A drug delivery system according to claim 51, wherein the active ingredient is a poorly soluble drug.

53. A drug delivery system according to claim 52, wherein the poorly soluble drug is in the form of nanoparticles.

54. A method for producing the drug delivery system of claim 41, comprising: (i) providing poorly water soluble drug dissolved in organic volatile solvent or mixture of organic volatile solvent with co-solvent that is either miscible or immiscible with water, optionally in the presence of at least one surfactant;(ii) mixing the drug containing solvent with an aqueous phase comprising at least one surfactant and optionally co-solvent and other emulsification aids at such conditions in which an oil-in-water nanoemulsion or microemulsion is formed;(iii) mixing the oil-in-water nanoemulsion or microemulsion with water-soluble bead forming polymers to produce a continuous phase of the emulsion which is capable of forming a bead;(iv) providing conditions enabling bead formation from the continuous phase of (iii) containing nano-microemulsion droplets;(v) optionally evaporating the volatile organic solvent and the water, thereby obtaining dry beads containing in the polymeric bead dispersed nanoparticles of poorly water soluble drugs.

55. A method according to claim 54, wherein the mixing of the poorly water soluble drug in an organic solvent occurs in the presence of at least one surfactant.

56. A method according to claim 54, wherein the drug containing solvent is mixed within an aqueous phase containing a surfactant, the aqueous phase further containing a co-surfactant and/or co-solvent, and/or electrolytes.

57. A method according to claim 54, wherein the nanoemulsion is prepared by homogenization by a high pressure homogenizer or by a phase inversion method.

58. A method according to claim 54, wherein the microemulsion is formed spontaneously by proper selection of the surfactants, solvent, co-solvent and co-surfactants.

59. A method according to claim 54, wherein at step (iv) the beads are incubated under suitable conditions and for suitable periods of time, with external crosslinking agents.

60. A method according to claim 59, wherein the polymer is an anionic polymer and external crosslinkers are multivalent cations selected from calcium, magnesium, copper, iron, barium and salts of these cations.

61. A method according to claim 59, wherein the polymer is a cation polymer and external crosslinkers are polyvalent anions selected from polyanions or sodium tripolyphosphate.

62. A method for producing a pharmaceutical composition comprising packing the beads obtained in claim 54 within a capsule or tablet.

63. A method according to claim 62, wherein disintegrator is added to the dry beads prior to packing the beads in a capsule or tablet.

64. A method according to claim 63, wherein the disintegrator is selected from chelators and molecules capable of replacing the crosslinking ions.