Patent Application
20100008983
Throughout this application various publications, published patent applications, and patents are referenced. The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133, 5,599,991, 5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061, 5,786,390, 6,316,504, 6,630,514 disclose R(+)-N-propargyl-1-aminoindan (“R-PAI”), also known as rasagiline. Rasagiline has been reported to be a selective inhibitor of the B-form of the enzyme monoamine oxidase (“MAO-B”) and is useful in treating Parkinson's disease and various other conditions by inhibition of MAO-B in the brain.
U.S. Pat. No. 6,126,968 and PCT International Publication No. WO 95/11016, hereby also incorporated by reference, disclose pharmaceutical compositions comprising rasagiline.
PCT International Publication No. WO 2006/014973, hereby incorporated by reference, discloses pharmaceutical compositions comprising rasagiline.
A concern in using monoamine oxidase (“MAO”) inhibitors is the risk of hypertensive crises, often called the “cheese effect.” (Simpson, G. M. and White K. “Tyramine studies and the safety of MAOI drugs.” J Clin Psychiatry. 1984 July; 45 (7 pt 2): 59-91.) This effect is caused by inhibition of peripheral MAO. A high concentration of peripheral MAO is found in the stomach.
A further concern in Parkinson's disease patients is that many patients suffer from delayed gastric emptying (Pfeiffer, R. F. and Quigley, E. M. M. “Gastrointestinal motility problems in patients with Parkinson's disease: Epidemiology, pathophysiology, and guidelines for management,” CNS-Drugs, 1999, 11(6): 435-448; Jost, W. H., “Gastrointestinal motility problems in patients with Parkinson's disease: Effects of antiparkinsonian treatment and guidelines for management”, Drugs and Aging, 1997, 10(4): 249-258). Delayed gastric emptying (prolonged gastric residence) can be a cause of increased inhibition of peripheral MAO, and can contribute to the cheese effect.
The subject invention provides a pharmaceutical composition comprising a liquid fill which includes an amount of rasagiline mesylate, a shell comprising gelatin surrounding the liquid fill, and an enteric coating surrounding the shell.
FIG. 1—Comparison of dissolution in pH=6.2, BUFFERRED vs. NO BUFFERRED.
FIG. 2—Double coat, MODIFIED, 6.0 mg/cm2, pH=6.2.
FIG. 3—Double coat, MODIFIED vs. Double coat, NO MODIFIED, pH=6.2.
The subject invention provides a pharmaceutical composition comprising a liquid fill which includes an amount of rasagiline mesylate, a shell comprising gelatin surrounding the liquid fill, and an enteric coating surrounding the shell.
In an embodiment of the pharmaceutical composition, the liquid fill further comprises a hydrophilic or amphiphilic solvent or surfactant.
In another embodiment, the hydrophilic or amphiphilic solvent or surfactant is selected from the group consisting of: polyethylene glycol, propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives and ethanol.
In yet another embodiment, the hydrophilic solvent is polyethylene glycol.
In yet another embodiment, the hydrophilic solvent is polyethylene glycol 400.
In another embodiment of the pharmaceutical composition, the pharmaceutical composition is free of propylene glycol.
In yet another embodiment of the pharmaceutical composition, the liquid fill further comprises an anti-oxidant.
In an embodiment, the antioxidant is water-soluble.
In another embodiment, the antioxidant is selected from the group consisting of: propyl gallate, BHA, BHT and ascorbic acid.
In yet another embodiment, the antioxidant is BHA.
In yet another embodiment of the pharmaceutical composition, the shell further comprises a plasticizer.
In an embodiment, the plasticizer is selected from the group consisting of glycerol and sorbitol or a combination thereof.
In yet another embodiment of the pharmaceutical composition, the enteric coating comprises Poly(methacrylic acid, ethyl acrylate) 1:1.
In an embodiment, the enteric coating further comprises a plasticizer.
In another embodiment, the plasticizer is polyethylene glycol 20,000.
In yet another embodiment of the pharmaceutical composition, a non-enteric subcoat is present between the gelatin shell layer and the enteric coating layer.
In an embodiment, the total weight of the subcoat and enteric coating layer is less than 10% of the total capsule weight.
In another embodiment, the weight of the enteric coating layer is less than 8% of the total capsule weight.
In yet another embodiment, the weight of the enteric coating layer is less than 6% of the total capsule weight.
In yet another embodiment, the weight of the enteric coating layer is less than 4% of the total capsule weight.
In yet another embodiment, the gelatin shell layer comprises a cross-linking inhibitor.
In yet another embodiment, cross-linking inhibitor in the gelatin shell layer is glycine.
In yet another embodiment, the subcoat comprises hydroxypropyl methyl cellulose.
In another embodiment of the pharmaceutical composition, when placed in a basket apparatus in 500 mL of aqueous buffered solution at a pH of 8.2 at 75 revolutions per minute, not less than 85% of the rasagiline in the pharmaceutical composition is released into solution within 30 minutes.
The subject invention also provides a pharmaceutical composition comprising a liquid fill which includes an amount of rasagiline mesylate, a shell comprising gelatin surrounding the liquid fill, and an enteric coating surrounding the shell, when placed in a basket apparatus in 500 mL of aqueous 0.1 N HCl at 37° C. at 75 revolutions per minute, not more than 10% of the rasagiline is released into solution in 120 minutes and when the composition is subsequently placed in a basket apparatus in 500 mL of aqueous buffered solution at a pH of 6.8 at 37° C. at 75 revolutions per minute, not less than 75% of the rasagiline is released into solution within 90 minutes.
In an embodiment of the pharmaceutical composition, when placed in a basket apparatus in 500 mL of aqueous 0.1 N HCl at 37° C. at 75 revolutions per minute, not more than 10% of the rasagiline is released into solution in 120 minutes and when the composition is subsequently placed in a basket apparatus in 500 mL of aqueous buffered solution at a pH of 5.2 at 37° C. at 75 revolutions per minute, not more than 10% of the rasagiline is released into solution within 90 minutes.
The subject invention further provides a pharmaceutical composition comprising a liquid fill which includes an amount of rasagiline mesylate, a shell comprising gelatin surrounding the liquid fill, and an enteric coating surrounding the shell, when placed in a basket apparatus in 500 mL of aqueous 0.1 N HCl at 37° C. at 75 revolutions per minute, not more than 10% of the rasagiline is released into solution in 120 minutes and when the composition is subsequently placed in a basket apparatus in 500 mL of aqueous buffered solution at a pH of 6.2 at 37° C. at 75 revolutions per minute, not less than 75% of the rasagiline is released into solution within 45 minutes.
MAO inhibitors that selectively inhibit MAO-B are largely devoid of the potential to cause the “cheese effect”. Nonetheless, the possibility exists that delayed gastric emptying of R-PAI may contribute to this phenomenon. Therefore, a main goal in developing the formulations of the current invention was to develop a delayed release, enteric coated formulation comprising rasagiline mesylate in an amount equivalent to 1 mg of rasagiline base which would release the active ingredient in the duodenum and the jejunum, past the stomach.
During the development of the formulations of the current invention, it was determined that the formulations should meet the criteria of bioequivalence to the known, immediate release rasagiline mesylate formulations (as disclosed in example 1) in a single dose bio-equivalence study in healthy subjects. These criteria include similarity of Cmax and AUC0-t (area under the curve) within the range of 80-125% within a 90% confidence interval between the new formulations and the known, immediate release formulations. The difference between the two formulations should be evident in bioequivalence studies as a difference in tmax. In other words, the mean pharmacokinetic profile of the formulations of the current invention should match the mean pharmacokinetic profile of the formulations of the known immediate release formulation, with the exception of the tmax which should be greater for the delayed release formulation than for the immediate release formulation.
The reason for attempting to match the mean Cmax and AUC0-t of the known immediate release formulation (i.e. to formulate a delayed release formulation that is bioequivalent) is that the efficacy of the immediate release formulation has been proven, and it is likely that the efficacy of the formulation relates to its mean Cmax and/or AUC. (Arch Neurol. 2002; 59:1937-1943.)
In order to reach this target, development was directed toward enteric coated capsules having a liquid fill, filled with rasagiline mesylate, with an enteric coating which allows release of the rasagiline mesylate in a specific range of pH. This specific pH range would prevent the formulation to release rasagiline mesylate in the stomach, and would allow the formulation to release rasagiline mesylate quickly under the physiological conditions of the intestine.
In PCT application publication WO 2006/014973, enteric-coated rasagiline mesylate pharmaceutical formulations were disclosed. In the disclosed formulations (Example 1, 2 and 4) methacrylic acid—ethyl acrylate copolymer (1:1) 30% dispersion, known as Eudragit® L-30 D-55 was used. As evident in the above-mentioned publication, these formulations were indeed delayed-release formulations as shown by their dissolution profiles and by the in-vivo data, however, the pharmacokinetic profile, in terms of mean Cmax did not match the pharmacokinetic profile of the immediate release rasagiline mesylate formulations.
The excipient methacrylic acid-ethyl acrylate copolymer (1:1) 30% dispersion, known as Eudragit® L-30 D-55, used in the above-mentioned publication WO 2006/014973, when applied as an aqueous dispersion either on tablets or on spheres prevents dissolution of the coated composition at low acidic pH. The structure of this polymer is as follows:
The ratio of the free carboxyl groups to the ester groups is approximately 1:1. The average molecular weight is approximately 250,000.
When this excipient is used in an aqueous dispersion or in an organic solution and formed into a film coating of a pharmaceutical formulation, it is intended to dissolve at a pH of about 5.5. (Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms; Second Edition, Revised and Expanded. Ed. James W. McGinity, 1997.)
It is probable that these prior art formulations began to dissolve in the stomach, perhaps in the presence of food which can raise the pH in the stomach, and continued to dissolve over a prolonged period of time in the duodenum and the jejunum. The prolonged dissolution period could explain why the Cmax of these prior art formulations was significantly lower than the Cmax of the immediate release formulations to which they were compared. In addition, once the coated tablet formulations began to disintegrate, the rasagiline mesylate was not dissolved, therefore it was not available for immediate absorption in the intestine. An advantage of the formulation of the instant invention is that the rasagiline mesylate is already dissolved in solution within the capsule, so once the capsule passes into the intestine and the pH rises, the capsule will rapidly break open, releasing dissolved rasagiline mesylate into the intestine, thereby allowing for rapid absorption.
Achieving the goal of a delayed-release pharmaceutical formulation in which the Cmax is similar to the corresponding immediate-release formulation is not trivial. In general, when delayed release formulations are compared to their immediate release counterparts in bio-studies, the Cmax of the delayed release formulations are lower than the Cmax in the corresponding immediate release formulations. (Mascher, et al. Arneimittelforschung. 2001; 51(6): 465-9. Behr, et al. J. Clin Pharmacol. 2002; 42(7): 791-7.)
Gelatin capsules, used as a pharmaceutical dosage form or with food supplements, consist of a gelatin shell surrounding a core filled with the composition being delivered. Hence, gel capsules may be a hard capsule, filled with solid or semi-solid fill and formed by two partial moieties of the shell, which are joined in order to create the final shell of the capsule, or a soft capsule, where a liquid or semi-liquid fill is encapsulated by a one piece gelatin shell, and optionally, even so-called caplets, where a modified tablet is covered by gelatin shell.
Soft gelatin capsules are produced by injecting the liquid or semi-liquid fill between two gelatin strips, either by discontinuous formation or by continuous formation (i.e., rotary-die process). During the manufacturing process, both strips of the gelatin gel have to be lubricated by a suitable lubricant in order to avoid early sticking of the fresh gelatin gel to the machine parts or to each other. Suitable lubricant agents include pharmaceutical oils, as for example mineral oils (paraffin oil), synthetic oils (silicone oil) or vegetable oils (coconut oil, corn oil).
Liquid or semi-liquid fills for the soft gelatin capsules are divided into two basic groups according to their miscibility with water (Hom and Jimerson, Capsules, Soft. In: Encyclopedia of Pharmaceutical Technology. Vol. 2, Swabrick and Boylan (Eds), Marcel Dekker, New York and Basel, 269-284, 1990; and Lachmann, Theory and Practice of Industrial Pharmacy, 2nd Ed. Lea and Febiger, Philadelphia, 1986):
The fills containing only the compounds from the first group do not mix with water. After their encapsulation into the fresh gelatin gel, the excess water leaves the gel and enters the inner fill. The excess water is almost completely resorbed by the gelatin shell of the capsule during the drying process, until equilibrium with the surroundings is achieved. Conversely, fills containing compounds from the second group are able to take in and absorb a certain amount of water, which can enter the fill of the capsule after its encapsulation. The resorption process is more difficult for these fills and equilibrium achievement is conditioned by the HLB (hydrophilic to lipophilic balance) value and absorption hysteresis curve for gelatin shells of concrete composition (York, J. Pharm Pharmacol. 33:269-273, 1981).
Besides the two groups of fills for soft gelatin capsules mentioned above, there exists another group of compounds or their mixtures, which are totally inappropriate for being filled into gelatin capsules.
Both the capsules with water immiscible liquids and the capsules with water miscible liquids can be enteric-coated for drug delivery to the small intestine. As the lipophilic drugs formulations in water immiscible liquids are rarely susceptible to decomposition in the acidic environment of the stomach, the enteric coating is especially suitable for drugs that have their absorption window rather small (in the proximal intestine), or, which are susceptible to decomposition in acidic environment of the stomach, and concurrently are formulated in water miscible liquids, as for example, polyethyleneglycols and non-ionogenic surfacial active material (surfactants).
Normally, enteric-coated products for drug delivery to the small intestine dissolve rapidly in the in-vitro dissolution tests (in 40-60 min). However, there are two major limitations of practical use of enteric-coated products for drug delivery to the small intestine:
Numerous factors affect the dissolution of enteric-coated solid dosage forms, namely tablets and hard gelatin capsules, can be affected by the thickness of the coating polymer, by the appropriate selection of the plasticizer for the coat, and by using two coating layers (the subcoat and the upper coat).
On the other hand, the use of soft or hard gelatin capsules is often affected by the risk of gelatin cross-linking. The employment of gelatin capsules as an oral delivery means is known in the pharmaceutical arts. In pharmaceutical applications, soft gelatin capsules are especially suitable for oral administration of lipophilic active substances. However, once the cross-linking of the gelatin occurs, the gelatin shell becomes less soluble in an aqueous medium, especially in an acidified water medium. The cross-linking delays the disintegration of the gelatin shell, which subsequently delays the dissolution of the inner content of the capsule as compared with a similar capsule not exposed to long time storage or stress-conditions which promote cross-linking.
Therefore, it is necessary when the gelatin capsule contains a component which promotes cross-linking in the gelatin shell to prepare a formulation which will not induce delayed disintegration and/or delayed dissolution of the inner content of the capsule following storage or after exposure to stress conditions.
The shells of both hard and soft gelatin capsules are susceptible to cross-linking. Cross-linking has been demonstrated by a prolongation of the dissolution time and release of drug substance. The delay is attributed to only partial dissolution of the gelatin shell (in case of soft gelatin capsules, the dissolved part is the outer layer of shell). In some instances, the inner layer of the gelatin shell forms a thin film, called a pellicle, which remains intact and envelopes the inner volume of the capsules. This effect is described by Carstensen and Rhodes (Drug Dev. Ind. Pharm, 19(20): 2709-2712, 1993) or Bottom, et al., (J. of Pharm. Sci., 86(9): 1057-1061, 1997).
Considering relatively small intensity of mixing in dissolution apparatus, the rupture of gelatin shell containing the pellicle is worsened and delayed as well and it is the cause of high variability of results of the dissolution test.
There are presently two basic methods described in the literature addressing the dissolution problems of soft gelatin capsules. These methods include:
(a) demonstrating that the altered dissolution profiles obtained from cross-linked gelatin capsules is a laboratory phenomenon by utilizing in vivo bioequivalence and/or clinical studies which attempt to demonstrate that actual biological availability of test agents are not negatively affected by the cross-linking; and
(b) elimination of the causes of cross-linking, namely (i) elimination of physical conditions, which promote the cross-linking, (ii) elimination of substances, which promote the cross-linking (cross-linking promoters), and (iii) addition of cross-linking inhibitors (where the most effective action is concurrent combination of these precautions).
The instant invention provides a solution to the problem of peripheral MAO inhibition by providing pharmaceutical dosage forms comprising rasagiline which are adapted to inhibit the release or absorption of rasagiline in the stomach (i.e. delay the release of rasagiline until at least a portion of the dosage form has traversed the stomach). This avoids or minimizes absorption of rasagiline in the stomach, thereby avoiding or minimizing the potential cheese effect.
In addition, the present invention provides a very effective way to prevent the cross-linking of gelatin in soft gelatin capsules by the use of cross-linking inhibitor and inhibitor enhancer.
In all of its aspects, the present invention provides an oral pharmaceutical dosage form useful for treating a condition selected from the group consisting of: Parkinson's disease, brain ischemia, head trauma injury, spinal trauma injury, neurotrauma, neurodegenerative disease, neurotoxic injury, nerve damage, dementia, Alzheimer's type dementia, senile dementia, depression, memory disorders, hyperactive syndrome, attention deficit disorder, multiple sclerosis, schizophrenia, and affective illness, but with a reduced risk of peripheral MAO inhibition that is typically associated with administration of rasagiline with known oral dosage forms.
Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al., issued Oct. 3, 2000. Techniques and compositions for making dosage forms useful in the present invention are described, for example, in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, melting agents, and plasticizers. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like, suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol and the like.
The basket-type apparatus used in this invention is the apparatus 1 described in the United States Pharmacopeia, 29th Edition, chapter 711. The apparatus is constructed as follows:
The assembly consists of the following: a covered vessel made of glass or other inert, transparent material; a motor; a metallic drive shaft; and a cylindrical basket.
The vessel is partially immersed in a suitable water bath of any convenient size or placed in a heating jacket. The water bath or heating jacket permits holding the temperature inside the vessel at 37±0.5 during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom and with one of the following dimensions and capacities: for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its inside diameter is 98 mm to 106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its inside diameter is 145 mm to 155 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4%. Shaft and basket components of the stirring element are fabricated of stainless steel type 316 or equivalent.
Unless otherwise specified in the individual monograph, use 40-mesh cloth. A basket having a gold coating 0.0001 inch (2.5 μm) thick may be used. The dosage unit is placed in a dry basket at the beginning of each test. The distance between the inside bottom of the vessel and the basket is maintained at 25±2 mm during the test.
Within the context of this invention, dissolution is measured as an average measurement of 6 pharmaceutical dosage forms, for example, capsules or tablets.
This invention will be better understood from the experimental details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Rasagiline immediate release tablets were prepared using the ingredients listed in Table 1.
Rasagiline mesylate, mannitol, half of the colloidal silicon dioxide, starch and pregelatinized starch were mixed in a Diosna P-800 mixer for about 5 minutes. Water was added and the mixture was mixed further. The granulate was dried and the remainder of the colloidal silicon dioxide was added. The granulate was ground in a Frewitt mill and stearic acid and talc were added. The granulate was mixed for five minutes in a tumbler and was tableted.
Rasagiline capsules were prepared according to example 3 in PCT application publication WO 2006/014973.
These capsules were tested for dissolution in 500 ml of various aqueous acidic media made from phthalate buffer adjusted to the target pH from 2.4 to 3.6 using HCl solution and adjusted to the target pH of 4.2 to 5.2 using NaOH solution.
The capsule formulation begins to dissolve after 60 minutes in medium with a pH of 5.2. This may explain the lower Cmax value in a single dose, crossover comparative pharmacokinetic study in 12 healthy male volunteers in the fasting state attributed to this formulation when compared to the immediate release formulation of example 1. It is likely that the dissolution of this formulation occurs slowly from the time the formulation enters the duodenum until the formulation proceeds in the intestine to the jejunum. Without being bound by theory, this may be attributed to the fact that the capsule disintegrates in the stomach and the coated pellets travel at different speeds through the intestine, releasing the rasagiline over a longer period of time, over a larger intestinal surface area.
Solubility of Rasagiline mesylate was evaluated in various solvents in order to determine which solvents would be suitable for developing a fill for rasagiline mesylate soft gelatin capsules.
Rasagiline Mesylate was found to be soluble in solvents such as Caprylocaproyl macrogol-8 glyceride, glyceryl mono- & dicaprate, polyoxyethylene sorbitan fatty acid esters, 2-(2-ethoxyethoxy)ethanol, polyoxyethylene castor oil derivatives, polyethylene glycol, propylene glycol, and ethanol.
Solutions with PEG, PG and Tween 80, hydrophilic solvent solutions, were shown to have a decrease in assay in accelerated conditions solvent solutions.
In parallel, four Rasagiline mesylate (1.56 mg per/capsule) solutions were prepared and Dissolution tests of hard gelatin capsules filled by these solutions were performed in two media: 0.1N HCl and buffer phosphate pH 6.8. The dissolution results are presented in the following tables:
No difference of dissolution results was observed in 0.1N HCl between the formulations, as dissolution was rapid. In buffer phosphate pH 6.8 solution the highest dissolution profile was observed for formulation included 10% PG and PEG 400. For hydrophobic solvent-based formulation much slower dissolution results were obtained.
Based on the enhanced dissolution of Rasagiline Mesylate hydrophilic solvents in phosphate buffer at pH of 6.8, it was decided to attempt to enhance stability of those formulations.
Based on the instability in hydrophilic solvents, it was decided that an antioxidant should be added to stabilize the formulations.
A solution was prepared using Rasagiline Mesylate in a concentration of 15.6 mg/g solvent, 10% ethanol, 0.01% BHT, and the remainder was propylene glycol. This solution was placed in accelerated conditions of 40° C. for 1 month, and 55° C. for 2 weeks. The solution was found to be stable, and the rasagiline mesylate concentration did not decrease.
A similar formulation was prepared, but without the BHT. This formulation was stable at 55° C. for 2 weeks, but at 40° C. for 1 month, the rasagiline mesylate concentration decreased by 3.6%.
This experiment indicates that anti-oxidants, such as BHT, can be useful in stabilizing solutions of rasagiline mesylate in hydrophilic solvents such as propylene glycol.
Additional solutions were prepared with additional antioxidants as in table 7. Their stability (rasagiline content by assay) is shown in table 8. Initial concentration of Rasagiline Mesylate in the solutions was 15.6 mg/g.
Rasagiline content by assay was found to be stable in solutions C and D. Rasagiline content of solution C decreased by 2.7% after 2 months storage at 40° C., but the amount of impurities was significantly lower than it was without antioxidants.
Based on solution D, a new formulation was prepared with addition of Glycerin. Glycerin is used as an effective plasticizer for soft gelatin capsules containing hydrophilic fills due to the strong intermolecular interactions between the hydroxy-groups of glycerin and the hydrophilic groups on gelatin. Glycerin and water may migrate from the shell to the hygroscopic fill. In order to balance this migration process and prevent embrittlement of the shell glycerin was added to the filling solution.
Additional solutions were prepared as described in table 9. Their stability (rasagiline content by assay) is shown in table 10.
As shown in Table 10, solution F was found to be stable.
Gelatin Capsules were Prepared using the Following Fill:
The Soft Gelatin Capsule Shell was made from the Following Excipients:
Capsule preparation itself consists of three steps—fill preparation, gelatin preparation and encapsulation of the fill preparation into the gelatin forming soft gelatin capsules.
Under ambient condition in appropriate container Propylene Glycol 400, Glycerol 85% and Buthylhydroxyanizol, were mixed and Rasagiline Mesylate was added and mixed with the mixer for approximately 30 min to obtain a clear yellowish solution. Then the solution was filtrated through a 5 μm filter to remove potentially presented un-dissolved components using nitrogen overpressure. Finally the fill was evacuated for approximately 15 minutes to remove dissolved gas from the solution.
Water, glycerol, propylene glycol and sorbitol in appropriate bin were heated up to 88° C. Gelatine and glycine were transferred in to the bin and temperature was maintained at approx. 77.5° C. for 20 minutes and slowly mixed. Then the gelatine was de-aerated while being vigorously mixed to achieve final viscosity in the range 19,000-23,000 mPa·s. In the end the gelatine solution was maintained melted in the bin heated up to 60° C. until it processing to soft gelatine capsules.
Using standard encapsulation machine (for instance: Sankyo, Bochang, Pharmagel, Technophar) from the melted gelatin two gelatin ribbons were prepared by pouring melted gelatin on to lubricated cooling drums. Drums can be cooled by different media—besides air also various liquids are suitable to make a convection of excess heat away. Ribbons with precise thickness were then transferred into cutting dierolles and a welding wedge equipped with a filling nozzle, where capsules were cut off the ribbons, filled with 150±10 mg of the fill and welded. Fresh capsules were then pre-dried and polished with paraffin oil in tumbler dryer for approx 3 hours. Pre-dried capsules were then transferred on plates and dried for 3 days in a drying room (RH <20%; temperature <25° C.) to achieve content of water in the fill <10%. Dried capsules were optically controlled and then washed in appropriate solvent (n-heptan, ethanol, etc.) to remove polishing agent from the surface.
3-oval capsules (oval shape) weighing 257.7 mg, each containing 1.56 mg of rasagiline mesylate were manufactured. They were subsequently coated with a single layer of the following Eudragit-based coat.
Appropriate portion of water was pre-heated up to 80° C., then glyceryl monostearate was added together with Tween 80 and mixed for approx 10 minutes (approx. 4000 rpm) until smooth emulsion was achieved. Meanwhile, in a separate vessel, 1 part of Polyethylene glycol 20,000 was mixed with approx 5 parts of water and homogenized for 20 minutes (approx. 150 rpm). Eudragit L30 D55 was poured into appropriate container and slowly neutralized with 1N NaOH. After that, the solution containing glyceryl monostearate was added, homogenized for a while and then PEG 20,000 solution was added to complete the coating solution. When it was completed, the admixture was homogenized for approx 20 minutes (approx 250 rpm).
Coating was performed in RAMA COTA coater equipped with standard Glatt spray gun. Inlet air 40±5° C., outlet air 30±5° C., atomization air pressure 3±1 bar, drum speed 12±3 rpm. The capsules were sprayed at a low spray rate, of 2-3 g/min.kg. The coating was applied in various thicknesses.
The dissolution in 0.1 N HCl was determined, 500 ml, 37° C., 75 rpm; apparatus 2 with sinkers.
These capsules were not resistant to acid conditions, even when the coating was increased to 9.20% by weight, and even when dried under additional drying conditions.
Microscopic examination showed that the lack of acid resistance stems from pinholes in the apical area of the oval capsules, which is the part of the capsule having the most mechanical strain.
Gelatin Capsules were Prepared using the following Fill:
The Gelatin Coating was made from the following Excipients Gelatin Composition:
Gelatin capsules were prepared in the same manner as described in Example 6.
3-round capsules weighing (248.9 mg) were manufactured. The capsules were round to prevent mechanical stress and creation of the pinholes during dissolution which can cause early leakage. Round shape of capsules also helps to get more uniform coat on the capsules.
Enteric coating: These capsules were subsequently coated with either a single layer 8% by weight, based on Eudragit coat (the same as described in Example 6), or by a double layer, which is 4% of Hypromellose 2910 (Pharmacoat 606) and 4% Eudragit.
Tne dissolution percent in 0.1 N HCl was determined. The capsules were in 0.1 N HCl for 120 minutes, then subsequently transferred to phosphate buffer at a pH of 6.8.
Dissolution was performed in USP Dissolution apparatus 1 (Basket). First 2 hours in 500 ml 0.1 M HCl, then in Dissolution Medium II: 500 ml Buffer pH 6.8. The buffer pH 6.8 is prepared as follows: dissolve 27.22 g of KH2PO4 in water and dilute with water to 1000 ml; place 250 ml of this solution in a 1000 mL volumetric flask add 112 mL of aqueous NaOH (0.2M), then add water to volume. Time for Dissolution medium II: 90 minutes; stirring rate: 75 rpm.
The results show that a single layer coat, even while added at 8% weight, was not sufficient to prevent dissolution of Rasagiline Mesylate in acidic conditions. In both the single layer and double layer coating, dissolution in the pH of 6.8 medium was not rapid. After 60 minutes in phosphate buffer at a pH of 6.8, the dissolution was less than 25% for both single layer and double layer coating.
This indicates that in order to achieve fast dissolution in aqueous neural pH, it is beneficial to use a fill based on primarily hydrophilic excipients.
In addition, these capsules showed some dissolution in 0.1N HCl after 120 minutes. The amount of dissolution in the single layer was greater than in the double layer, indicating that a primary non-enteric coating (subcoat) applied directly to the gelatin coating is beneficial in enhancing the acid resistance of the capsules.
Gelatin Capsules were Prepared using the Following Fill:
Capsules were prepared in the same way and under the same conditions as described in Example 6.
The dissolution percent in 0.1 N HCl was determined. The capsules were in 0.1 N HCl for 120 minutes, then subsequently transferred to phosphate buffer at a pH of 6.8.
Dissolution was performed in USP Dissolution apparatus 1 (Basket). First 2 hours in 500 ml 0.1 M HCl, then in Dissolution Medium II: 500 ml Buffer pH 6.8. The buffer pH 6.8 is prepared as follows: dissolve 27.22 g of KH2PO4 in water and dilute with water to 1000 ml; place 250 ml of this solution in a 1000 mL volumetric flask add 112 mL of aqueous NaOH (0.2M), then add water to volume. Time for Dissolution medium II: 90 minutes; stirring rate: 75 rpm.
The Gelatin Shell was made from the following Excipients Gelatin Composition:
The capsules are prepared in 5 steps: fill preparation, gelatin preparation, encapsulation and drying, coating and packaging.
Under ambient condition in appropriate container Polyethylene glycol 400, Glycerol 85% and Buthylhydroxyanizol were mixed. Rasagiline Mesylate was added and the mixture was mixed for approx. 30 min to attain a clear yellowish solution. Then the solution was filtrated through a 5 μm filter to remove un-dissolved components using nitrogen overpressure. The solution was then evacuated for approx. 15 minutes to remove dissolved gas from the solution
Gelatin Preparation:
Part of water, glycerol and sorbitol were heated up to 88° C. in an appropriate bin. Glycine was dissolved in remaining portion of water and pH of the solution was adjusted with sodium hydroxide to pH 8.0+/−0.1. Gelatin was then transferred in to the bin and temperature is maintained at approx. 77.5° C. for 20 minutes and the mixture was slowly mixed. The solution was de-aerated whilst vigorously mixing to achieve final viscosity in the range 19,000-23,000 mPa·s. The solution was maintained melted in the bin heated up to 60° C.
Using a standard encapsulation machine (Sankyo, Jp), 2 gelatin ribbons were prepared by pouring melted gelatin onto lubricated cooling drums. Ribbons with precise thickness were then transferred into cutting die-rolls and welding wedge equipped with a filling nozzle, where capsules were cut off the ribbons, filled with 150±10 mg of the fill and welded shut.
Fresh capsules were pre-dried and polished with paraffin oil in tumbler dryer for approx 3 hours (with temperature not exceeded 30° C.). Pre-dried capsules were transferred on plates and dried for 3 days in a drying room (RH<20%; temperature <25° C.) to achieve content of water in the fill <10%.
Dried capsules were visually checked and then washed in n-heptan to remove polishing agent from the surface.
Coating was performed in Glatt GMPC II machine. Capsules were transferred in to a coating drum pre-heated up to 37° C. Hypromelose dissolved in water was used as the 1st coat (desired spray rate >4 g/min.kg or >20 g/min for 5 kg batch). The desired thickness of the 1st coat is approx 2-3% by weight of the capsules.
After the first coat the capsules were dried for max 60 minutes and 37° C.
As a second coat, Eudragit L30D 55 dispersion with plasticizer and glidant was applied; (desired spray rate >4 g/min.kg or >20 g/min for 5 kg batch); and a desired thickness of the second coat of approx 2.8-3.8% by weight, preferably 3.3% by weight was applied (total thickness of 2 coats all together is approx. 5.8±20%).
Capsules were dried for max 60 minutes and 37° C. and then cooled down below 30° C. Coated capsules were subjected to optical control to remove defective capsules.
Coated capsules were packed into desired packaging, preferably into packaging which ensures moisture protection. Al/Al blisters are preferred, however also other types of moisture protection packs are suitable—following examples of packaging possibilities illustrate (without limitation) additional possibilities: container/closure systems consisting of containers made from various types of material (glass, HDPE, PP, PE, PS, PVC, PVdC, Al etc) with appropriate closure system optionally also equipped with moisture controlling device and optionally additional moisture controlling device enclosed into the container, blister systems consisting from two foils usually made from HDPE, PP, PE, PS, PVC, PVdC, All materials optionally packed in additional moisture protecting container or foil pack.
Al/Al blisters were packed with capsules after 1 month in accelerated conditions of 40° C. at 75% relative humidity. The capsules were found to have 0.10% total impurities, and a Rasagiline Assay of between 90.0-110.0%.
The dissolution percent of the capsules was determined. The capsules were in 0.1 N HCl for 120 minutes, then subsequently transferred to phosphate buffer at a pH of 6.2.
Dissolution was performed in USP Dissolution apparatus 1 (Basket). First 2 hours in 500 ml 0.1 M HCl, then in Dissolution Medium II: 500 ml Buffer pH 6.2. The buffer pH 6.2 is prepared as follows: dissolve 20,415 g of KH2PO4 in water and 121.5 ml 0.2M NaOH and in volumetric flask add water to volume 3000 ml. Time for Dissolution medium II: 90 minutes; stirring rate: 75 rpm.
The dissolution percent of the capsules was determined. The capsules were in 0.1 N HCl for 120 minutes, then subsequently transferred to phosphate buffer at a pH of 6.8.
Dissolution was performed in USP Dissolution apparatus 1 (Basket). First 2 hours in 500 ml 0.1 M HCl, then in Dissolution Medium II: 500 ml Buffer pH 6.8. The buffer pH 6.8 is prepared as follows: dissolve 27.22 g of KH2PO4 in water and dilute with water to 1000 ml; place 250 ml of this solution in a 1000 mL volumetric flask add 112 mL of aqueous NaOH (0.2M), then add water to volume. Time for Dissolution medium II: 90 minutes; stirring rate: 75 rpm.
This formulation was found to resist dissolution in 0.1 N HCl for 120 minutes, and to dissolve quickly in pH 6.2 and 6.8 conditions almost entirely within 45 minutes.
The following tables compare the results of dissolution with and without modification of the gelatin shell.
The cores of tablets tested in Table 11a were prepared as described in the Example 1 with the ingredients in the following table:
The cores of the tablets were then coated with an enteric coating according to following table:
The capsules tested in Table 11b were prepared as described in the Example 7.
The capsules tested in Table 11c were prepared as described in the Example 9.
The results in the above tables show that the use of cross-linking inhibitor in the gelatin shell in combination with inorganic base, together forming a buffer of alkalic pH (e.g. pH 8.5) and increasing ionic strength of the gel solution, helps in achieving faster disintegration and dissolution of enteric-coated soft gelatin capsules.
In general, when delayed release formulations are compared to their immediate release counterparts in bio-studies, the Cmax of the delayed release formulations are lower than the Cmax in the corresponding immediate release formulations. As illustrated in the above Examples 1-10, achieving a delayed-release pharmaceutical formulation in which the Cmax is similar to the corresponding immediate-release formulation is not trivial.
It has been surprisingly found from the results of Examples 1-9 that the formulations of the current invention meet the criteria of bioequivalence to the known, immediate release rasagiline mesylate formulations in a single dose bio-equivalence study in healthy subjects. These criteria include similarity of Cmax and AUC0-t (area under the curve) within the range of 80-125% within a 90% confidence interval between the new formulations and the known, immediate release formulations.
As shown in the results of Example 10, it has also been surprisingly found that the use of cross-linking inhibitor helps to achieve faster disintegration and dissolution of enteric-coated soft gelatin capsules. However, the role of cross-linking inhibitor used herein is not only prevention of cross-linking reaction. In combination with weak organic acids and inorganic salts, cross-linking inhibitor modifies the pH and ionic strength of the liquid phase in the gelatin gel. Specifically, it has been found that increased ionic strength and higher buffer capacity of the gelatin shell causes the migration of solvent from the dissolution media to the gelatin shell and/or inner coating layer, which is eroding, swelling and disintegrating faster than without such a modification.
Even more surprisingly, it has been found that that increased ionic strength and higher buffer capacity of the (inner) gelatin shell causes not only the migration of solvent from the dissolution media to the gelatin shell and/or inner coating layer, but also the formation of swelled gel-liquid phase at higher pH level, which assists the dissolution of the outer coat. As a result, not only the disintegration of the gelatin shell is facilitated, but the onset of dissolution of the whole coating system is much more rapid.
The application claims benefit of U.S. Provisional Application No. 61/131,566, filed Jun. 10, 2008, the contents of which are hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61131566 | Jun 2008 | US |
