COMPOSITION OF EXCIPIENTS FOR IN-VITRO STABILIZATION OF FELODIPINE IN A CONTROLLED RELEASE FORMULATION
BACKGROUND OF THE INVENTION
1, Field of the Invention
The present invention relates to a composition of excipients for preparing a stable, controlled release formulation of felodipine to a stabilized orally administered dose of felodipine. Degradation is minimized to acceptable levels at zero time and as a function of prolonged exposure to heat and humidity.
2. Background of the Art
A commercially available orally administered dose of felodipine is Plendil® ER Tablets which are believed to be prepared by the innovator according to U.S. Patent No. 4,803,081. The drug is dissolved or dispersed in an effective amount of a semi-solid or liquid nonionic solubilizer (active solubiliser and the solubiliser ore in preferred ratio range from 1:2 to 1:6). A preferred solubilizer is polyethoxylated castor oil (e.g., Cremophor® RH 40 by BASF). Unfortunately, Cremophor® is implicated in embryotoxicity and allergic reactions. Sharma, A. ed. Al (1997) Int. J. Cancer 71, 103-107.
BRIEF SUMMARY OF THE INVENTION
A controlled release matrix containing felodipine was designed based on traditional excipients . Felodipine was unstable in the presence of such excipients. Future formulations were stabilised based on cyclodextrins and an alkanising agent such as magnesium trisilicate. Magnesium trisilicate was added to serve as a source of OH". It is hypothesized that hydroxyethyl cellulose hydrates and absorbs the hydrated OH which migrate to the weakly acidic B-cyclodextrin. As the felodipine particle can be non-covalently bound to B-cyclodextrin, for example during microfluidization, the felodipine particle is protected from any possibility of degradation.

The aqueous process of granulation is environmentally compatible in contrast with solvent-based granulation processes disclosed in the prior art. The use of dextrins, and especially 6-cyclodextrin to stabilize pharmaceutical compounds' and compositions, especially through microfluidization of Felodipine, has not been reported in the literature.
DETAILED DESCRIPTION OF THE INVENTION The current invention recognizes reasons for the undesirabil'ity of Cremophor® in pharmaceutical compositions where it can be eliminated and therefore has developed a novel process known as "Microfluidization" for achieving bioequivalence to Plendil®. The process is described in copending U.S. Patent Application Serial No. 09/340917, filed June 28, 1999, which application is incorporated herein by reference, titled "Preparation of Micron-Size Pharmaceutical Particles by Microfluidization." That application describes a process whereby for micronized feed materials, microfluidization is carried out at low pressures (e.g., about 3,500 to 7,000 or 4,000 to 6,000 pounds per square inch) to effectively meet the 6-12 micron particle size range, using 1 -3 passes.
For the design of monophasic drug delivery systems of very slightly soluble drugs such as felodipine, a monophasic particle size distribution, ranging from 1-3 microns, is used to design a swellable, erosion rate-controlled drug delivery system, by using a combination of a highly swellable non-ionic polymer and hydrophific insoluble excipients. The geometry of the drug delivery system (e.g., the tablet), for example, at a constant polymer (binder): excipient :drug ratio, can be modified from a generally spherical matrix (e.g., diameter of 10.6 mm and thickness of 6.46mm, approximately 288mm2) to a more cylindrical form (e.g., diameter of 12.92 mm and a thickness of 4.58 mm, approximately 342mm2) to generate a larger surface area and a shorter distance for erosion or diffusion of the delivery system. The resultant effect of this particular modification is an acceleration of

matrix erosion. The success of any drug delivery system is governed by the drug absorption performance, which is in turn at least a particle function of the drug release rate and characteristics. This is particularly true where the drug permeability after oral administration is not a rate-limiting step in the process of the distribution of drug molecules in the body.
Using the process of microfluidizatioa an aqueous medium is selected for wet-micronization of the drug/excipients based on the particle size distribution (PSD) of the feed material (unmicronized vs. micronized) and the targeted particle size distribution either by having all components such as the drug, a dextrin (especially a cyclodextrin such as B-cyclodextrin), hydroxypropyl cellulose, Cremophor RH-40 (a surface active agent), and Simethicone (an antifoaming agent) in the feed material or by separating the operation into two phases, namely microfluidization of the drug with water and S-cyclodextrin and subsequent blending of the outflow material with a separately prepared dispersion of hydroxypropyl cellulose in water, and finally the addition of Simethicone. This operation facilitates reduction of mean particle size of the drug and B-cyclodextrin and creates a smooth latex-like microsuspension. In the presence of dextrins, particularly cyclodextrins, particle sizes even in the nanometer range (e.g., below lOOOnm, e.g., less than 500nm, less than 400nm, and between 20 and 1000, or between 30 and 500nm are novel and may be produced according to the present invention (with or without the presence of surface active agents or surface modifying agents). The dextrins, as noted, remain as particles within the microfluidization system and the products. The dextrin may or may not be separable from the pharmaceutical particles. This is in contrast to the literature knowledge of the performance of B-cyclodextrin in other processing environments. For example, in Pharmaceutical Technology, June 1991, Jozsef Szejtli states that Cyclodextrins (CDs) are enzymatically modified starches made up of glucopyranose units. Three different CDs are known.... All of the CDs are crystalline and non-hygroscopic, and they feature a

cylinder-shaped, macro-ring structure with a large internal axial cavity. The outer surface of a CD molecule is hydrophilic, but the internal cavity is a apolar. When this cavity is filled with a molecule of another substance, the result is an inclusion complex. No covalent bonding is involved. This is in contrast to the B-cyclodextrin remaining on the surface of the pharmaceutical particles, even if some amount of inclusion complex may be formed with the drug by the B-cyclodextrin remaining on the surface of the article, e.g., the hydrophobic Felodipine particle.
The discussion rate of a solid is described by the Noyes-Whitney equation:
D = Diffusion coefficient
A = Surface area of the dissolving solid
V = Volume of the dissolving solid
H = Diffusion layer thickness
Cs = Solute concentration in the diffusion layer
C = Solute concentration in the bulk
During early phase of dissolution, Cs » C and is essentially equal to the
saturation solubility C,. Under these conditions and at constant
temperature agitation, the above equation reduces to


Dissolution rate expressed in the above equation is termed the intrinsic dissolution rate and is characteristic of each solid compound in a given solvent, under fixed hydrodynamic conditions. The intrinsic dissolution rate is a fixed volume of solvent generally expressed as mg dissolved in min"1 cm"2.
A basic problem of poorly soluble drugs is an insufficient bioavailability, which is related to low saturation solubility Cs and dissolution rate dc/dt. The attempts to solubilize the drugs in micelles or with cyclodextrins are of limited success for many drugs. A better approach is to microfluidize (wet-micronize) the hydrophobic drug in the presence of optimum carriers. The primary drug particle approaches about 1-3 micron size, preferably an amorphous form, and a hydrophilic surface for optimum dissolution and absorption. The sizes described herein for particles, whether for the pharmaceuticals or for the dextrins , are non-aggregated particle sizes. Unless otherwise stated, the sizes are weight average particle sizes. The ranges may alternatively be applied to number average particle sizes, usually where fewer than 10% by number of the particles exceed the stated average size by more than 25%.
The aqueous solubility of felodipine was determined to be 0.001% at all pHs, respectively. Intrinsic dissolution rates of felodipine was calculated to be 0.00086mg min"1 cm"2. The media was 500 ml phosphate buffer with 1% sodium lauryl sulfate, Type II, with dissolution assisted by the use of a paddle. Based on this data a 10-20 micron range for felodipine will exhibit dissolution rate-limited adsorption.
The use of antifoaming agents, such as silicone compounds, fluorinated compounds, such as Simethicone and FC-40 manufactured by Minnesota Mining and Manufacturing Co. (although there are many chemical classes of materials known in the art for this purpose) has already been briefly referred to. These compounds provide a significant benefit to the process performance that is unrelated to any surface active effect they may have on the relationship of the pharmaceutical to the liquid carrier in the microfluidisation process ,

when the particles are provided in the aqueous carrier, significant amounts of air or other gas is carried with the particles, Because of the small size of the particles, the air or other gas is not easily shed from the surface of the small particles, it is carried into the carrier liquid, and foaming can occur in suspension, This is highly undesirable in the microfluidization process and adversely affects the ability of the process to control the particle size and other benefits, Therefore it is desirable, either before any microfluidization occurs or shortly after initiation of the microfluidization process, to introduce an anti-foaming agent to the particles and/or to the particles and liquid (water) carrier. It is particularly desirable to add the particles and antifoaming agent to the liquid carrier and allow a significant dwell time (e.g., at least 5 minutes, preferably at least 10 or 15 minutes, up to an hour or more) to allow the air or other gas to disassociate itself from the surface of the particles, Some mild agitation to 'shake-off' the bubble from the surface of the particles may be desirable, but is not essential. This defoaming may occur directly within a storage or feed tank for use in the microfluidization system or may be done at another time prior to introduction of the suspension into the microfluidizer. The defoaming agents, some of which are surfactants (a term that is actually quite broad in scope), may also be used, and are preferably used in amounts that are much smaller than the concentrations or volumes that are usually necessary for effective surface active properties, For example, defoaming agents may be used in w/w/percentages of the solution in ranges, for example, of 0.0005% to 0.2%, 0.005 to 0.1%, or 0.005 to 0.08% by weight of the total solution/dispersion, while surface active agent tend to be used in much higher concentrations (even through some disclosures may include levels as low as those described herein for defoaming agents).
It is important to note that the dextrin is introduced into the carrier drug
particle system as a solid particle itself. The dextrin remains as a particle
in the process, even if there is some breakdown or minor dissolution of
' the dextrin. This is important to recognize since the dextrin cannot act

as a surface modifying agent, does not form a coating on the surface of the pharmaceutical particle, and remains only non-covalently associated with the hydrophobic, water-insoluble drug particle during and after the microfluidization process. The pharmaceutical hydrophobic, relatively water-insoluble drug, the dextrin or both may be added to the suspension or used to form the suspension in any size particle, as for example, from about 1 to 50, 1 to 100, to 1 to 200 micrometers in size. The dextrin particles may be larger or smaller than the drug particles. The dextrin may be added to the drug in a ratio of drug to dextrin of from about 1:50 to 50:1. With certain of the drug actually tested particularly practicable ranges include from 1:50 to 20:1 (drug/dextrin, particularly B-cyclodextrin), 1:30 to 5:1, 1:25 to 1:1, and l:15tol:2.
A stable felodipine formulation may be based on a matrix composed of micronized and microfluidized felodipine, a cyclodextrin, preferably B-cyclodextrin, a binder (e.g. hydroxypropyl cellulose, preferably Klucel® LF) and a matrix former (e.g. hydroxyethyl cellulose, preferably Natrosol 250M and optionally preferably and alkaline excipient, preferably magnesium trisilicate, and an optional lubricant, preferably magnesium stearate.
The granules are prepared by placing B-cyclodextrin and hydroxyethyl cellulose in the granulator. The drug dispersion (containing the binder, e.g., hydroxypropyl cellulose) containing magnesium trisilicate is sprayed onto the blended material.The granules are dried to a moisture content of not more than 2%. The granules are lubricated with colloidal silicon dioxide, and magnesium stearate. The product is compressed using 11 mm standard concave punches . Thereafter the core are coated with a novel cosmetic membrane composed of low viscosity hydroxyethyl cellulose (Natrosol® 250L), disclosed in a separate invention disclosure.
The felodipine in each manufactured dose may comprise from 2.5mg to lO.Omg based on label claim in the formulation.

The cyclodextrin may be α,β, or y, while the preferred cyclodextrin is β-cyclodextrin.
Basic alkaline material may be selected from the group consisting of slats of strong basic cations and weak acidic anions such as Mg2\ Ca2+, or Al3+ and Co"2"3, CaO and Al203 at a preferred pH of 9 or greater. The alkaline material may also be selected from antacid materials such as magnesium oxide, aluminum hydroxide and magnesium hydroxide. Magnesium aluminum silicate (Veegum®) is also a suitable candidate for this function. The preferred basic alkaline material is magnesium trisilicate. The concentration in the matrix may range from 0.5 to 15% of the weight of the matrix. Preferred proportions are 2-10%, 3-8%, and 5%. To identify excipients which cause solid-state-degradations absed on a dry blend stability experimental design, stability of felodipine was studied at 60°C and 40°C/75% RH.
EXAMPLES
The specific nature of the composition of the present invention will be more fully apparent from consideration of the following specific, non-limiting examples of preferred embodiments of the invention.
Procedure 1 Bulk Drug Stability
Bulk drug stability was evaluated in solution and solid state by exposing test materials to accelerated conditions of 40°C and 75% RH. Additionally, the bulk drug was tested for photostability by applying an 8-hr exposure, 16-hr exposure and 24-hr exposure of UV radiation (at 254nm and 365nm).
It was concluded based on the results of these treatments that felodipine molecule was stable for three months in solution and solid states.
Procedure 2 Dry Blend Stability
Stability of felodipine blended with various excipients in 1:5 ratio was tested at 40°C and 75% RH and 60°C. Excipients studied were B-

cyclodextrin, hydroxypropyl cellulose (Klucel® LF), dicalcium phosphate dihydrate (Emcompress®), hydroxyethyl cellulose (Natrosol® 250M), magnesium stearate, colloidal silicone dioxide, stearic acid and a blend of all components.
Conclusion : A clearer picture emerged at 60°C. The rank order of instability was stearic acid > blend of all components > dicalcium phosphate dihydrate > silicone dioxide > 3-cyclodextrin.

Example 1 Blend Stability in Suspension Form
Stability of felodipine suspension with different excipients was studied in a ratio of 1:5 (drug : excipient). Results are compiled in Table 1. Table : 1 Influence of 3-cyclodextrin on suppressing the "Formation of impurities" from felodipine.


Conclusion : As 6-cyclodextrin is present in all experiments, it is concluded that it forms a saturated dispersion and possibility clathrates of various materials including felodipine and dicalcium phosphate dihydrate present in the suspension. This treatment protects the drug from degradation.
Example 2 The objective of this study was to determine the optimum quantities of
magnesium trisilicate required to stabilize the formualtion. Table 2 : Optimization of Quantity of Magnesium Trisilicate

Example 3 Formulation FERT-16 contained 6-cyclodextrin along with a minor amount (1% of Magnesium Trisilicate in slurry form) of a water insoluble alkaline excipient. The results of accelerated study are presented
below:
Table 5 : Product - Stability using B-cyclodextrin


Example 4 Formulation FERT-019 contained 6-cyclodextrin along with a major amount (13.3% magnesium trisilicate) of a water insoluble alkaline excipient which is located in the "Bowl charge". The results of accelerated study are presented below.

DISCUSSION Bulk drug stability was evaluated in solution and solid state by exposing compositions in these states to accelerated conditions of stability (40°C' and 75% relative humidity). Additionally, the bulk drug in solid state was tested for photostability (8 hour, 16 hour and 24 hour exposure under UV irradiation).
Stability of Felodipine blends with different excipients was studied at 60°C and 40°C/75% RH, in a ratio of 1:5 (Felodipine : Excipient). Excipients studied were B-cyclodextrin (Cavitron®), Hydroxypropyl Cellulose (Klucel® LF), Dicalcium phosphate dihydrate (Emcompress®), Hydroxyethyl cellulose (Natrosol® 250M), Magnesium stearate (Hyqual®), Colloidal silicon dioxide (Aerosil® 200), Stearic acid (Hystren®), and total blend (blend of all excipients). Stability of Felodipine suspension with different excipients were studied at 45°C using the same ratio as in the dosage form. None of the excipients showed any degradation.
It must be noted that each formulation contained B-cyclodextrin. This was a surprising observation. It may be explained, however, on the basis of non-covalent bonding of B-cyclodextrin with Furthermore, it is observed that even through the LOD of these granulations when exposed to 75% RH was quite high (FERT-016 @ 11.51% w/w and FERT-019 @ 9.65 w/w), the procedure proves that moisture alone does not degrade felodipine.

The role of magnesium trisilicate is to create an alkaline micro-environment for the protection of felodipine molecules by providing hydroxyl ions; there is a migration of hydroxyl ions seeking a relatively lower pH, moving toward weakly acidic 6-cyclodextrin which is non-covalently bound to felodipine and hence the protection of felodipine from undergoing degradation.
CONCLUSIONS
1. Felodipine bulk molecule would be rendered stable according to the invention for three months at 40°C/75% RH.
2. Felodipine excipients drug stability at 60°C showed a rank order of instability : stearic acid > blend of all compounds > dicalcium phosphate dihydrate > silicon dioxide > B-cyclodextrin.
3. Felodipine excipient suspension stability at 45°C showed no instability indicating that non-covalently bonded 6-cyclodextrin to felodipine protected the latter from degradation.
4. Magnesium trisilicate creates an alkaline microenvironment for the protection of felodipine molecule from degradation.

WHAT IS CLAIMED IS :
1. A stabilized composition for oral administration of felodipine comprising particles of felodipine, cyclodextrin, pharmaceutically acceptable water-dispersible or water-soluble binder, and an alkaline agent.
2. The stabilized composition of claim 1 wherein said cyclodextrin is present as particles.
3. The stabilized composition of claim 1 wherein said cyclodextrin is non-covalently bonded to said felodipine particles.
4. The stabilized composition of claim 2 wherein said cyclodextrin is non-covalently bonded to said felodipine particles.
5. The stabilized composition of claim 1 wherein said cyclodextrin comprises beta-cyclodextrin.
6. The stabilized composition of claim 2 wherein said cyclodextrin comprises beta-cyclodextrin.
7. The stabilized composition of claim 4 wherein said cyclodextrin comprises beta-cyclodextrin.
8. The stabilized composition of claim 1 comprising particles of felodipine, cyclodextrin, a pharmaceutically acceptable binder comprising hydroxypropyl cellulose or water-dispersible binder, an alkaline agent and a pharmaceutical lubricant.
9. The stabilized composition of claim 8 wherein said alkaline agent comprises salts, inorganic hydroxides, metal silicates or inorganic oxides selected from the group consisting of a) weak acidic anions and strong basic cations, b) metal oxides c) metal silicates and d) metal hydroxides.
10. The stabilized composition of claim 8 wherein said alkaline agent is
selected from the group consisting of salts, oxides and silicates of
magnesium, calcium or aluminum.

11. A composition providing a stabilized controlled release a swelling/erosion rate controlled film coated tablet of felodipine comprising a stabilizing excipient and a source of hydroxyl ions, which composition, when exposed to high temperature and high humidity is found to be stable for at least one month after exposure to accelerated storage conditions of 40°C and at a relative humidity of 75%, comprises less than or equal to being not more than 2 percent by weight of total impurities in the drug-substance.
12. The composition of claim 11, where said stabilizing excipient comprises a cyclodextrin.
13.The composition of claim 11, where said cyclodextrin comprises B-cyclodextrin.
14. The composition of claim 11, where said source for hydroxyl ions comprises a basic alkaline material which may be selected from the group consisting of salts of strong basis cations and weak acidic anions such as Mg2+, Ca2+, or Al3+ and CaO and Al203 at a preferred pH of 9 or greater..
15. The composition of claim 12 wherein said cyclodextrin is selected from the group consisting of a-cyclodextrin, 8-cyclodextrin, dimethyl - B-cyclodextrin and hydroxyethyl - B-cyclodextrin.
16. The composition of claim 13 wherein B-cyclodextrin is present as from 10-80% by weight of solids compressed into a tablet dosage form.
17.The composition of claim 14, wherein said alkaline material comprises magnesium trisilicate,
18. The composition of claim 17, wherein magnesium trisilicate is present as from 0.5 to 2.5% by weight of solids compressed into a tablet form.
19. The composition of claim 11 in a combination with ACE inhibitor enalapril maleate.

20. The composition of claim 1 wherein said binder comprises hydroxypropyl cellulose.
21. The composition of claim 2 wherein said binder comprises hydroxypropyl cellulose.
22. The composition of claim 4 wherein said binder comprises hydroxypropyl cellulose.
23. The composition of claim 6 wherein said binder comprises hydroxypropyl cellulose.
24. The composition of claim 10 wherein said binder comprises hydroxypropyl cellulose.
25. The composition of claim 12 wherein said binder is present which comprises hydroxypropyl cellulose.
26. The composition of claim 14 wherein a binder is present which comprises hydroxypropyl cellulose.
27.The composition of claim 17 wherein a binder is present which comprises hydroxypropyl cellulose.
28. The composition of claim 18 wherein a binder is present which comprises hydroxypropyl cellulose.
29. The composition of claim 19 wherein a binder is present which comprises hydroxypropyl cellulose.