Patent Application
20050118264
The present invention relates to extended release compositions comprising as active compound Venlafaxine Hydrochloride.
Venlafaxine Hydrochloride is an antidepressant having formula 1
being designated (R/S)-1-[2-(dinehylamino)-1-(4-methoxyphenyl)ethy1]cyclohexanol hydrochloride or (±)-1-[a](dimethylamino)methyl]p-methoxybenzyl cyclohexanol hydrochloride, having the empirical formula of C17H27NO2 hydrochloride and molecular weight of 313.87.
Venlafaxine hydrochloride is a white to off white crystalline solid with a solubility of 572 mg/ml in water (adjustment to ionic strength of 0.2 M with sodium chloride). Its octanol: water (0.2 M sodium chloride) partition coefficient 0.43. Effexor XR the Brand product is formulated as an extended release capsule for once a day oral administration.
The drug release has so far been controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Known capsules containing Venlafaxine Hydrochloride comprise amounts equivalent to 37.5 mg, 75 mg, or 150 mg of Venlafaxine. The inactive ingredients are mainly cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, and titanium dioxide.
Controlled or extended release dosage forms of medicament are conventionally produced as hydrogel matrix based tablets. At this technology the controlled release dosage forms are simply prepared by mixing the active material with the appropriate rate of controlling polymers and then that mixture is compressed into the desired controlled release tablets. The rate controlling polymers are normally termed as hydrogels. Examples of such polymers are cellulose ethers such as ethyl cellulose or hydroxypropylcellulose. Patents describing preparation methods of such dosage forms are described for example in U.S. Pat. No. 4,966,768 or U.S. Pat. No. 4,389,393.
In some cases, for example with very water soluble active materials and with relatively high doses it is not feasible to produce tablets which enable appropriate control on the drugs release. This is the case, for example with Venlafaxine Hydrochloride.
In such a case a suitable approach is encapsulating the drug and producing extended release capsules dosage forms. When preparation of such dosage forms is considered, the preferred way is to mix the active ingredient with at least one binding agent to form a uniform mixture which is later moistended with water or with an appropriate organic solvent to form an extrudable plastic mass, from which small particles, cylinders shape (1 mm diameter) of drug/matrix are extruded, chopped into appropriate lengths and converted to spheroids using spheronization equipment. These spheroids are further dried and than film coated with an appropriate polymer to form a film with the desired release patterns. The most widely used excipient in the extruding process is microcrystalline cellulose in its different grades usually water is used for the wetting process.
Polymers widely used for coating are ethyl cellulose or Eudragit (Ammonio methacrylate copolymer, type A or B). Water soluble ingredients are normally mixed with the ethyl cellulose or with other hydrophobic polymers, such as pore forming agents to assist the control on the drugs release through the hydrophobic coating layer. The water soluble ingredients such as hydroxypropyl cellulose or polyethylene glycol may serve as plasticizers as well.
Venlafaxine Hydrochloride has so far been formulated into a controlled release dosage form with the ability to provide in a single dose a therapeutic blood serum level of the drug over a twenty four hour period. By this method, tighter plasma therapeutic range control can be obtained and a multiple dosing is avoided in this manner. The sharp peaks and troughs in blood plasma drug levels are avoided as well.
With the conventional release dosage forms of Venlafaxine Hydrochloride (tablets), peak blood plasma levels appeared after 2-4 hrs, in contrast to the extended release dosage forms, when plasma levels of Venlafaxine Hydrochloride rose after administration for between five to eight hrs (average—6) and than begin to fall through a protracted, substantially linear decrease from the peak plasma level for the reminder of the period, maintaining therapeutic level of the drug during the entire twenty four hours period.
In WO 99/22724 (AHP, Sherman) a detailed description of preparating an encapsulated dosage form (coated spheroids) of Venlafaxine Hydrochloride is provided. By the method described therein, a spheroid core is prepared by extruding and spheronizing a mixture of the drug with microcrystalline cellulose, and than coating it with an ethyl cellulose hydroxypropylcellulose mixture.
This dosage form provides an extended release product with the following in vitro dissolution specifications:
These dissolution characteristics are pH, RPM independent.
In the present invention an alternative once daily bioequivalent formulation to the innovators one (Effexor XR, described in WO 99/22724) has been developed.
As already mentioned, with high dose water soluble product such as Venlafaxine Hydrochloride (150 mg), the usual preferred way of encapsulating it is by preparing and coating an appropriate beads, using the extrusion spheronization process.
In the present invention the microencapsulation has been changed, i.e. is being performed by layering the drug over an inert pareil core, and than coating it with an appropriate polymeric mixture.
The present invention thus consists in an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.
The composition preferably comprises 30-60% of Venlafaxine Hydrochloride per weight of the total dosage form.
In a preferred embodiment of the present invention, the Venlafaxine Hydrochloride is suitably connected to a binder, said binder may be e.g. polyvinyl pyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. The composition preferably comprises 0.5%-10% of the binder per weight of the total dosage form.
Advantageously the non pareil inert core is an inert sugar core, a microcrystalline cellulose or the like. The composition preferably comprises 30-60% of the core per weight of the total dosage form.
Alternatively the drug might be sprayed as it is and the water is then used as binding enhancement agent.
Advantageously the coated core is coated with an isolating/protecting/separating layer, which layer is suitably composed of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystallinecellulose, carrageenan, GMS etc. The composition preferably comprises 0.5-10% of the isolating layer per weight of the total dosage form.
The core or the isolating layer is coated then with an additional polymeric layer which enables the controlled release of Venlafaxine Hydrochloride. Said additional polymeric layer is composed, e.g. of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer. Said polymeric layer is suitably sprayed over the coated non pareil layer or over the isolating layer.
Appropriate coating polymers are, e.g. Eudragit, cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetate, etc. Their suitable plasticizers are, e.g. castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phtalate, glyceryl trihepthanoate, triethyl citrate, etc.
The coating polymeric layer may also be a wax based coating.
The composition preferrably comprises 2-15% of the hydrophobic polymer per weight of the total dosage form; and preferably 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.
The above processes are conventional processes that may be performed in a fluid bed coater with a bottom spraying mechanism.
In the composition according to the present invention, preferably not more than 40% of the drug are released after two hours, not more than 60% released after 4 hours and not more than 80% after 8 hours.
The compositions obtained are suitably, e.g. filled into hard gelatin capsules or compressed into tablets.
This formulation has an identical in vitro dissolution profile as Effexor XR (see Sherman, WO99/22724). They are not sensitive to any changes in dissolution conditions. It is bioequivalent to Effexor XR 150 mg caps.
The coating process being used to produce the composition according to the present invention is more efficient than the method being used at the Sherman patent. Moreover, it enables the preparation of the drug in a single type of equipment, e.g. a fluid bed coater.
The present invention will now be illustrated with reference to the following examples without being limited by them.
The process preparing the composition according to the present invention is suitably performed as follows (all temperatures are given in degrees centigrade):
Stage 1: Components—Non pareils 25/30 150 gr
Stage 2: Components—150 gr layered pellets from stage 1
At the end of the spray process the composition for 10 minutes without nozzle with 30 cfm.
Stage 1: components—Non pareils (inert sugar pellets) 150 gr
Stage 2: components—150 gr. layered pellets from stage 1
The coating process was performed in a “4” fluid bed coater made by Coating Place Inc. USA.
Stage 1: components—Non pareils 25/30—150 gr
Stage 2: components—150 gr layered pellets from stage 1
The coating process was performed in a “4” fluid bed coater, made by Coating Place Inc. USA.
Stage 1: components—Non-pareils 25/30—150 gr.
Stage 2: components—150 gr. pellets from stage 1.
All processes were performed in a “4” fluid bed coater, made by Coating Place Inc. USA.
Stage 1: components—150 gr. Non pareils 25/30
Stage 2: components—150 gr. Pellets from stage 1
Stage 3: components—Pellets from stage 2
| Number | Date | Country | Kind |
|---|---|---|---|
| 146462 | Nov 2001 | IL | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL02/00890 | 11/7/2002 | WO |
