FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION FORMULATION OF BENZAZEPINE DERIVATIVES"
We, EMCURE PHARMACEUTICALS LIMITED, of ARC-H, P-2, I.T. - B.T. Park Phase - II, M.I.D.C, Hinjwadi, Pune - 411057, Maharashtra, India.
The following specification describes the invention:

FORMULATION OF BENZAZEPINE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a controlled release formulation for oral administration comprising galanthamine and to a process for preparation of such controlled release formulation.
BACKGROUND OF THE INVENTION
Galanthamine, i.e. (4aS,6R,8aS)-4a,5,9,10,l l,12-hexahydro-3-methoxy-l l-methyl-6H-benzofuro[3a,3,2-efJ[2]benzazepin-6-ol, is an alkaloid of the morphine group, which can be obtained from plants viz., snowdrops {Galanthus woronowii, G. nivalis etc.) and other Amaryllidaceae. Racemic Galanthamine (I) is extracted from daffodil bulbs. (-) Galanthamine (II), and derivatives thereof, are useful for the treatment of mild to moderate dementia of the Alzheimer's disease. Galanthamine and its salt have also been employed in the treatment of a variety of disorders including alcoholism, nicotine dependence and mania.
OH OH
\ JL NMe \ Vj NMe
(I) (II)
Galanthamine hydrobromide salt is available in the USA as a film coated tablet of 4-mg, 8-mg and 12-mg strength, for twice a day oral administration under the trade name of Razadyne® (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Controlled release composition of Galanthamine hydrobromide is also available in the USA under the trade name of Razadyne ER®. The controlled release formulation is available in opaque hard gelatin extended release capsules of 8 mg (white), 16 mg (pink), and 24 mg (caramel) containing gelatin, diethyl phthalate, ethylcellulose, hypromellose, polyethylene glycol, titanium dioxide and sugar spheres (sucrose and starch) as inactive ingredients. The 16 mg capsule also contains red ferric oxide, whereas the 24 mg capsule contains red ferric oxide
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and yellow ferric oxide. (http://www.razadyne.com/
active/janus/en_US/assets/common/company/pi/razadyne.pdf)
Further, various attempts have been reported to improve the characteristics of a controlled release formulation of galanthamine, which are as follows:
i) Davis et. al. in CA 1,326,632 discloses a sustained release formulation wherein the particles of galanthamine hydrobromide are coated with polyvinyl pyrrolidone or any other suitable coating agent that is soluble in intestinal track;
ii) McGee et. al. in various published applications, namely WO 00/38686; US 2006/0062856; US 2006/0093671 discloses a controlled release formulation of galanthamine hydrobromide, wherein galanthamine hydrobromide along with a film forming water soluble polymer such as hydroxypropyl methylcellulose is coated on a central spherical inert core, which is then further coated with a release rate controlling membrane coating and then such coated spheres are filled in hard-gelatin capsules;
iii) Cantillion et. al. in US 2004/0097484 discloses a once a day pharmaceutical composition of galanthamine hydrobromide comprising a gelling agent, such as water soluble organic gums, natural clays, synthetic clays, to form a controlled release dosage form, such as a matrix, or diffusion-controlled composition;
iv) Similarly, Tang et. al. in another published application, US 2005/0142193 discloses Galanthamine formulations, which are substantially free of microcrystalline cellulose, lactose, and/or starch. This patent application further teaches that galanthamine pharmaceutical compositions comprising either lactose anhydrous or lactose monohydrate as diluent, and either powdered cellulose or microcrystalline cellulose as disintegrant result in segregation of the tablet excipients resulting in tablets having a variable composition; and
v) Boehm et. al. in another published application, US 2005/0191349 discloses sustained release as well as fast dissolve formulations of Galanthamine hydrobromide. The disclosed formulations are substantially free of a spray dried mixture of lactose monohydrate and microcrystalline cellulose and has a particular dissolution profile.
However, all the abovementioned pharmaceutical compositions of galanthamine have certain properties that are not ideal in all situations. For example, the formulation disclosed by
McGee et. al. comprises of drug substance coated on sugar spheres. These coated sugar
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spheres are then further coated with an optional seal coat and a release controlling membrane coat in specialized equipments such as in fluidized-bed granulator equipped with Wurster bottom spray. The overall process of preparing sugar spheres loaded with drug substance and then application of two or more coats, such as functional and non-functional coats, on sugar spheres is not only complex and tedious, but also highly time consuming.
The matrix tablet or diffusion-controlled composition as described by Cantillion et. al. has a major disadvantage that such a matrix formulation gets disturbed in the churning movement of food in the GI tract, which has in turn, the potential to change the predetermined release rate of drug substance from the drug product. The dosage form described above has further disadvantage in that the tablet or pill travels through the intestinal tract as one large mass constantly in physical contact with gastrointestinal tissue, thereby causing intestinal and gastric ulceration, occasional bleeding and other undesirable side effects such as nausea, vomiting and epigastric distress.
Further, the formulation disclosed in US 2005/0142193 is an immediate release formulation, releasing 90 % of drug substance after 10 minutes in 500 ml purified water. Again such a release profile is not particularly desirable in treatment of certain conditions such as Alzheimer's disease, wherein drug plasma levels are required to constantly maintain at or near steady state concentration. Thus, when immediate release formulation is utilized, then such formulation needs to be administered at least twice daily to achieve desired plasma level of drug substance. Such an administration schedule leads not only to patient discomfort, but also shows sharp increase and/or decrease in plasma levels of drug substance. Further the sharp increase or decrease in plasma levels of drug substance demands the close monitoring of the patient.
A preferred controlled release formulation of galantamine should release the required amount of drug in the initial hour, followed by slow release of the active agent over a longer duration of time, giving constant plasma level of drug substance and not the peak/trough pattern as observed with the immediate release formulation. The major purpose for developing prolonged release formulations of the drug is generally to maintain the blood concentration of the active ingredient at therapeutically effective levels.
In view of the above, there is a need for novel controlled release formulation of galanthamine hydrobromide, which is not only simple, economical and easy to manufacture, but also achieves the desired steady state plasma level of drug substance.
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OBJECTS OF THE INVENTION
An object of the present invention is to provide novel controlled release pharmaceutical composition comprising galanthamine.
Another object of the present invention is to provide novel controlled release pharmaceutical composition of galanthamine having a dissolution profile according to pharmacopoeial standards.
A further object of the present invention is to provide a simple, economical and less time consuming process for preparation of controlled release pharmaceutical composition comprising galanthamine.
Yet further object of the present invention is to provide a method for treatment of mild to moderate dementia of the Alzheimer's disease and related dementia by using the controlled release formulation of the present invention, without providing peak and trough in plasma levels of drug substance.
SUMMARY OF THE INVENTION
Present invention provides a solid oral dosage formulation of galanthamine, which comprises of galanthamine and one or more excipient materials. The unit dosage formulation of the present invention comprises of uncoated/seal coated tablet(s) and functional coated tablet(s).
The present formulation of galanthamine having suitable excipients is designed to obtain the desired result, i.e., a release of the required amount of drug in the initial period, followed by slow and constant release of the active agent, which is an ideal characteristics feature of a controlled release formulation.
By using a controlled release formulation of the present invention the period of time over which the therapeutic blood levels are maintained will be longer than that obtained with a conventional quick release galanthamine formulation. Therefore, beneficial therapeutic results are obtained with the formulation of the present invention by maintaining therapeutic level of galanthamine rapidly and continuously for a longer duration of time.
The therapeutic level of the drug as well as the period of time over which that level must be maintained can vary greatly, depending on the excipients used to prepare the pharmaceutical
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composition and vary further depending upon a range patient based factors such as the condition of the patient and the patient's reactivity to drug.
To obtain the desired therapeutic level of galanthamine, the oral formulation of the present invention, by virtue of having a uncoated/seal coated tablet of galanthamine, will quickly release a sufficient amount of galanthamine so as to swiftly obtain a therapeutic level and thereafter release galanthamine, from a functional coated tablet, at a rate which substantially matches the rate at which the galanthamine is being metabolized and eliminated. Accordingly, the formulation is designed to maintain a therapeutic level over a maximum amount of time based on the amount of galanthamine in the formulation and not to significantly exceed the therapeutic level.
The judicious selection of excipients as well as the ratio of functional coated to uncoated/seal coated tablet used in the pharmaceutical composition of the present invention, result in a formulation which allows galanthamine to be released in a controlled manner for absorption into the circulatory system. By maintaining a desired therapeutic level, the oral formulation of the present invention has potential to achieve better physiological effects.
Thus, in one aspect, the present invention protects galanthamine from degradation and allows it to be slowly released over a period of time.
In another aspect, the pharmaceutical composition of the present invention provides a solid dosage form, preferably a hard gelatin capsule, comprising uncoated/seal coated tablet and functional coated tablet.
DETAILED DESCRIPTION OF THE INVENTION
The controlled release pharmaceutical composition of the present invention comprises a combination of:
a) Functional coated tablets of galanthamine; and
b) Uncoated tablet of galanthamine.
By 'functional coating', it is meant to include a coating that modifies the release properties of the total formulation, for example, a sustained-release coating.
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As used herein the term 'uncoated tablet' means a non-functional coated tablet. The uncoated tablet could be a non-coated or a cosmetic coated tablet. A cosmetic coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
As used herein the term 'controlled release' means a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, extended, sustained, delayed or pulsed-release at a particular time. Moreover, controlled can mean that the release of the active agent is extended for longer time than that from an immediate-release dosage form having same amount of active agent.
The term galanthamine or galantamine or active agent, is meant to include galantamine or a pharmaceutically acceptable salts thereof, solvates, hydrates, polymorphs thereof, unless otherwise specified.
According to present invention, the uncoated tablet of galanthamine comprises of the active agent, and one or more suitable excipients in appropriate amounts. In particular, for preparing a uncoated tablet of galanthamine hydrobromide, lactose, preferably direct compressible lactose, is preferred whereas magnesium stearate is present as lubricant.
However, the present uncoated tablet galanthamine formulation may also, additionally contain one or more excipients that are normally employed in such pharmaceutical compositions, the only qualifications being that the excipients must not deleteriously affect the stability and intend of the pharmaceutical composition. Examples of excipients that can be employed include diluents, binders, disintegrant, lubricant, glidants, antiadherants, surfactants, water soluble polymers, water insoluble polymers.
A combination of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only few representative examples for each class of excipient are mentioned herein below:
Diluents for the formulations are inert substances that may be used as a vehicle for the active agent, optionally in conjunction with other excipients, as long as the resulting formulation meets the dissolution profile desired and/or is stable. Suitable diluents include, lactose-based
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materials such as spray dried lactose; cellulosic materials such as microcrystalline cellulose; starches including partially pregelatinized starch, pregelatinized starch, partially hydrolyzed starch, maize starch, potato starch, rice starch, wheat starch, and tapioca starch; sugar such as sucrose, dextrose, fructose, and the like; sugar alcohols such as mannitol, sorbitol, xylitol, and the like; saccharides polysaccharides such as maltodextrin and the like; dibasic calcium phosphate, calcium sulphate, and the combinations thereof.
Combination of two or more diluents can be used in the dosage formulations. When used, the total amount of diluents can be up to about 99 weight percent of the total weight of the formulation; specifically about 30 to about 98 weight percent; more specifically about 60 to about 97 weight percent; and yet more specifically about 80 to about 95 weight percent.
Binders may be, for example, starch, sugars, gums, hydroxypropyl methyl cellulose, hydroxyl propyl cellulose or the like. Certain traditional tablet diluents may also function as a disintegrant (e.g. starch), while other materials provide superior results as a disintegrant, for example, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, alginates, and the like. The disintegrant can be present in the formulations in an amount of about 0.01 to about 20 weight percent of the total weight of the formulation.
A lubricant and/or glidant can also be used in the dosage formulations to aid in the processing of powder materials. Exemplary lubricants include calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof.
Other optional additives to the dosage formulations include, for example, sweetening agent, flavoring agents, stabilizing agents, colorants, antioxidants and combinations comprising one or more of the foregoing additives.
The tablet according to the present invention may be prepared by using known process in the art. In general, a process for preparing storage stable galanthamine tablets includes the steps of:
(a) blending galanthamine in one or more of its form and its pharmaceutically acceptable salts with one or more pharmaceutically acceptable excipients to form a blend;
(b) compressing blend of step (a) to get a uncoated tablet;
(c) optionally applying a seal coat on tablet of step (b) to get a seal coated tablet;
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(d) applying a functional coat to get a functional coated tablet; and
(e) placing a uncoated tablet of step (b) or a seal coated tablet from step (c) and a functional coated tablet from step (d), in a proportion such that 15-35% of total dose of galanthamine is released immediately (immediate release) whereas 65 -85% of total dose of galanthamine is released in a controlled manner, in a unit dosage formulation, preferably hard gelatin capsule.
The approved dose of galanthamine hydrobromide for treatment of mild to moderate dementia of the Alzheimer's disease is 8 mg/day. A typical formulation according to present invention should have a release of 1.2 to 2.8 mg of galanthamine in the immediate manner and 5.2 to 6.8 mg of galanthamine in controlled manner.
The above disclosed process may further include any one of the features known to a person skilled in the art. For example, the process may further, optionally include granulating the blend of step (a) by a wet granulation process or a dry granulation process and further, the active pharmaceutical ingredients and suitable excipients may be agglomerated in the beads called as 'pellets', instead of tablet, by process of pelletization such as bailing, extrusion-spheronization, high-speed shear mixing.
The dosage formulation may comprise the active agent and excipients in the form of particles having a particle size distribution that allows for the ease of processing the material, for example into tablets, by direct compression techniques, without segregation of the excipients. The desired particle range of active agent and excipients and other components may be obtained by processes known in the art, including granulating, screening, milling, and the like.
When tablets are made by direct compression, the addition of lubricants may be helpful to promote powder flow and to prevent capping of the particle when the pressure is relieved. Preferred lubricant as described above includes magnesium stearate in an amount ranging from 0.001 to 1.0 percent.
Further, in the preferred embodiment, a process of preparing a pharmaceutical dosage formulation comprises passing of the galantamine or a pharmaceutically acceptable salt thereof and excipients though appropriate mesh sizes, either independently or collectively. The mixing or blending is done according to process known in the art such as by using a suitable blender or mixer etc.
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The galanthamine tablet, thus obtained can be, optionally, further coated with a seal coating agent that may or may not contain a colorant. Suitable seal coatings agent include cellulosic materials such as naturally occurring cellulose and synthetic cellulose derivatives such as hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose (CMC), sodium CMC, cellulose triacetate, cellulose sulphate sodium salt, and the like; acrylic polymers and vinyl polymers, for example polymethyl methacrylate, poly ethyl methacrylate, poly butyl methacrylate, poly isobutyl methacrylate, poly hexyl methacrylate, poly phenyl methacrylate, poly methyl acrylate, poly isopropyl acrylate, poly isobutyl acrylate, poly octadecyl acrylate, poly ethylene, poly ethylene low density poly ethylene, high density poly propylene, poly ethylene glycol, poly ethylene oxide, poly ethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate, poly vinyl chloride, polyvinyl pyrrolidone, and the like; proteinaceous materials such as gelatin, polypeptides and natural and synthetic shellacs and waxes; and combinations of the forgoing.
The seal coating material can be an immediate release coating chosen to provide a coated tablet having substantially the same dissolution properties as the corresponding uncoated tablet. An exemplary seal coating material includes hydroxypropyl methyl cellulose, especially Opadry YS-1-7006 clear®.
Generally, when a seal coating agent is used, it may be used in an amount of about 20 percent by weight or less of the weight of the tablet core; specifically about 15 percent or less; and more specifically about 10 weight percent or less. In one embodiment, the quantity of seal coating material should not be so high that the coating material impedes the release profile of the active agent when ingested or evaluated for dissolution profile.
Suitable methods can be used to apply the seal coating to the tablets. Processes such as simple or complex coacervation, interfacial polymerization, liquid drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, electrostatic deposition, may be used. A substantially continuous nature of the coating may be achieved, for example, by spray drying from a suspension or dispersion of the tablet in a solution of the coating composition including a polymer in a solvent in a drying gas having a low dew point.
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When a solvent is used to apply the coating, the solvent is preferably an organic solvent. The solvent may be selected from alcohols such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane, cyclohexane, and combinations comprising one or more of the foregoing solvents.
The uncoated tablet prepared according to present invention has a tablet weight ranging from 8 mg to 20 mg, preferably 10 mg to 15 mg, hardness in the range of 0.5 to 4 kg, thickness ranging from 1.8 to mm to 2.7mm, friability not more than 0.5% and a dissolution time less than 5 minutes.
Further, some of the uncoated or seal coated galanthamine tablets are further coated with a functional or release controlling coat. The functional coating is applied in such a way that the active agent is released at a substantially constant rate over a designated time period. Preferably, the controlled-release coating is capable of releasing the active agent at a substantially constant rate over a designated time period of from about 6, 8, 12, 24 and 48 hours. More preferably the designated time period is about 24 hours.
The controlled-release component can be hydroxypropyl methylcellulose ("HPMC"), hydroxypropyl methylcellulose phthalate ("HPMCP"), ethyl cellulose (EC), hydroxyethyl cellulose ("HEC"), hydroxy propyl cellulose ("HPC"), carboxy methyl cellulose ("CMC"), a methacrylic acid copolymer, cellulose acetate phthalate or mixtures thereof. The preferred controlled-release agent is ethyl cellulose, especially Surelease® .
Such functional coated tablet prepared according to present invention has tablet weight in the range of 10 mg to 22 mg, preferably 12 to 18mg, hardness in the range of 0.5 to 8.0 kg and thickness of 2.0 to 3.0 mm.
Generally, when a controlled release coating agent is used, it may be used in an amount of about 30 percent by weight or less of the weight of the tablet core; specifically about 20 percent or less; and more specifically about 14 weight percent or less. In the preferred embodiment, the amount of controlled release coating material should not be so great that the coating material impedes the desired release profile of the active agent when ingested or evaluated for dissolution profile.
The functional coated tablets and uncoated/seal coated tablet of galanthamine are provided in
a unit dosage formulation, preferably hard gelatin capsule, in such a ratio so as to achieve and
maintain the desired therapeutic level of galanthamine.
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The unit dosage formulation of the present invention, by virtue of having a uncoated/seal coated tablet of galanthamine, will quickly release a sufficient amount of galanthamine so as to quickly obtain a therapeutic level and thereafter release galanthamine, from a functional coated tablet, at a rate to maintain the obtained therapeutic level over a desired amount of time.
The weight ratio of uncoated/seal coated tablet and functional coated tablet that are placed in a unit dosage formulation is such that the final formulation has the Galanthamine (uncoated/seal coated tablet and functional coated tablet) in the ratio of 50 : 50 to 14: 86.
The desired ratio of uncoated/seal coated tablet and functional coated tablet that are placed in a unit dosage formulation is such that the final formulation releases 15-35% of total dose of galanthamine in immediate release manner, whereas 65-85% of total dose of galanthamine is released in a controlled manner. This could be achieved preferably by placing uncoated/seal coated tablet and functional coated tablet in a ratio so that 1.2 to 2.8 mg of galanthamine is released in the immediate manner, whereas 5.2 to 6.8 mg of galanthamine is released in controlled manner.
Similarly, pellets could be used for controlling drug release following coating with a suitable polymer coat, as described hereinbefore. A unit dosage form, preferably hard gelatin capsules filled with a mixture of coated and non-coated drug-containing pellets, similar to capsule filled with coated and uncoated tablets as disclosed hereinbefore, also gives programmed drug release after the capsule shell dissolves.
The preferred process used for preparation of pellets involves the separate processes of wet massing, followed by extrusion of this wet mass into rod-shaped granules and subsequent spheronization of these granules.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
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Examples:
Considering the feasibility of the pharmaceutical preparation, following examples were carried out. Example- 1:
A representative formulation of galanthamine hydrobromide, according to present invention is prepared as follows:
a) Preparation of Uncoated Tablets:
Requisite amounts, as mentioned herein below of Galantamine hydrobromide and lactose monohydrate were passed individually through Mesh # 40 and magnesium sterate through Mesh # 60. Mixture was blended thoroughly and compressed directly on a rotary tablet machine using 2.5 mm punch.
Sr No Ingredients Quantity (mg/tablet)
1 Galanthamine hydrobromide 2.56
2 Lactose monohydrate (DCL 15) 12.34
3 Magnesium stearate 0.10
b) Seal Coating:
5-10% w/w seal coat of Opadry YS -1-7006 was applied on the tablets by using suitable methods such as spray drying to give seal coated tablets. The unit formula for seal coating is as given herein below:
Sr No Ingredients Quantity (%W/W)
1 Opadry YS-1-7006 clear 10
2 Purified water Up to 100
c) Functional Coating:
15-25% w/w functional coat of Surelease was applied on the seal coated tablets by using suitable methods such as spray drying to give functional coated tablets. The unit formula for functional coating is as given herein below:
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Sr No Ingredients Quantity (%W/W)
1 Surelease 20
2 HPMC E3 1.5
3 Purified water Up to 100

d) Preparation of Solid Dosage Formulation:
The uncoated tablets and functional coated tablets were placed in the hard gelatin capsule in the ratio of 1:3.
Example- 2:
A representative formulation of galantamine hydrobromide, according to present invention is prepared as follows:
a) Preparation of Uncoated Pellets:
Requisite amounts, as mentioned herein below of Galantamine hydrobromide and microcrystalline cellulose were passed individually through Mesh # 20. Hydroxypropyl cellulose was dissolved in purified water. Galantamine hydrobromide and microcrystalline cellulose mixture with Hydroxypropyl cellulose solution were granulated and wet mass was passed through extruder equipped with 0.5 mm screen. Spherical pellets were obtained by spheronizing extrudes of galantamine hydrobromide in the spheronizer at 1500-2500 RPM. Talc could be used during spheronization to avoid adhesion of pellets.
Sr No Ingredients Quantity (% W/W)
1 Galantamine hydrobromide 5.0
2 Microcrystalline cellulose (Avicel pH 101) 90.5
3 Hydroxy propyl cellulose 4.0
4 Talc 0.5
b) Seal Coating:
5-15% w/w seal coat of Opadry YS -1-7006 was applied on the pellets by using suitable methods such as spray drying to give seal coated pellets. The unit formula for seal coating is as given herein below:
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Sr No Ingredients Quantity (%W/W)
1 OpadryYS-1-7006 clear 10
2 Purified water Up to 100
c) Preparation of Functional Coated Pellets:
15-30% w/w functional coat of Surelease was applied on the seal coated pellets by using suitable methods such as spray drying to give functional coated pellets. The unit formula for functional coating is as given herein below:
SrNo Ingredients Quantity (%WAV)
1 Surelease 20
2 HPMC E3 1.5
3 Purified water Up to 100
d) Preparation of Solid Dosage Formulation:
The uncoated pellets and functional coated pellets were placed in the hard gelatin capsule in a ratio so as to achieve 15-35% of total dose of galanthamine in an immediate release manner and 65 -85% of total dose of galanthamine in a controlled manner.

Dated this the 31st day of July 2006