Title of Invention

ENTERIC COATED FORMULATION FOR BISPHOSPHONIC ACID(S) FOR SALT(S) THEREOF

Abstract

A process for preparing a pharmaceutical composition comprising the steps of: providing an inert core, applying an active coating over said inert core to form an active core, applying a seal coating over said active core, and applying an enteric coating around the seal coating to form pellet; wherein the active coating comprises 5.36% by weight of at least one bisphosphonic acid or salt thereof such as alendronate sodium trihydrate, etidronate, clodronate, pamidronate, or ibandronate

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENS RULES, 2003 COMPLETE SPECIFICATION [See section 10, Rule 13] ENTERIC COATED FORMULATION FOR BISPHOSPHONIC ACID(S) FOR SALT(S) THEREOF; CIPLA LIMITED, A COMPANY INCORPORATED UNDER THE INDIAN COMPANIES ACT, 1913, WHOSE ADDRESS IS 289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI - 400 008, MAHARASHTRA, INDIA. GRANTED 28-11-2005 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. The present invention relates to pharmaceutical composition and a process for preparing the pharmaceutical composition containing the bisphosphonic acid(s) or salt(s) thereof, which composition will be used for the treatment of osteoporosis. The present pharmaceutical composition comprises by weight, about 5-40% by weight of an active ingredient selected from the group consisting of: 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, N-methyM-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid, 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonicacid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid, 1-hydroxy - 2- [3-pyridinyl] ethylidene-1, 1-bisphosphonic acid; 4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine; In the present invention the preferred bisphosphonic acid is 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid, i.e., alendronic acid; more preferable is its monosodium salt trihydrate, viz., alendronate sodium trihydrate, or other bisphosphonic acid(s) or salt(s) thereof, viz., etidronate, clodronate, pamidronate or ibandronate. Method of preparation of bisphosphonic acid may be found in, U.S. Pat. No. 3,962,432; U.S. Pat. No. 4,954,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,007; and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4- amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxybutylidene-1,1-blsphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,007, respectively. The disadvantages of all the above inventions are that the compositions release the active ingredient almost instantaneously causing oesophageal discomfort and ulceritis due to the release of the active ingredient in the upper Gastro Intestinal Tract (GIT). The medication has to taken on arising for the day at least 30 minutes before the first food, beverage or medication of the day with a full glass (200ml) of plain water only. The patients are advised to sit upright for about 30 minutes after the ingestion of medication and until their first food of the day. Patients are not allowed to take medication at bedtime or before arising on the day. According to the present invention, there is provided a pharmaceutical composition for oral administration substantially comprising a core having bisphosphonic acid or salts thereof, coated with an acid resistant coat thereby releasing the active ingredient only in the alkaline environment of the lower GIT. The purpose of the enteric coating employed in the present invention is to resist the acidic environment of the stomach, thus avoiding oesophageal irritation. Accordingly, the disadvantage of the prescribed method of taking the medication, as explained above, can be overcome by the present invention. The core containing of bisphosphonic acid(s) or salt(s) thereof can be coated with a hydrophilic polymer known in the art (seal coating) E.g. Hydroxy Propyl Methyl Cellulose (HPMC), Hydroxy Propyl Cellulose (HPC), Polyvinyl Pyrrolidone (PVP), Shellac, cellulose gums, xanthan gums, thereupon being coated with the enteric polymer. A wide variety of conventional enteric coatings may be employed in the present invention, including for example: cellulose acetate phthalate, Hydroxy propyl methyl cellulose phthalate (HPMCP); hydroxypropyl cellulose acetyl succinate; polyvinyl acetate phthalate; copolymerized methacrylic acid / methacrylic acid methyl esters, such as Eudragit L 12.5, Eudragit L 100 55 or Eudragit S 100; and mixtures thereof. The enteric coating may contain conventional plasticizers, pigments and /or dispersants, including for example polyethylene glycols, propylene glycol, triacetin, triethyl citrate, and Citroflex, dibutyl sebacate, glidants like talc, aerosil. The enteric coating can be applied in any suitable manner, for example in the form of an aqueous dispersion in water, or other dispersing medium, or in the form of a solution. It is preferred that a dispersion or solution of the enteric coating is treated with an alkali in order to neutralize at least part of any free acid content. The alkali may be, for example, a carbonate or hydroxide of sodium, potassium, magnesium or calcium. Pharmaceutical compositions according to the present invention may comprise one or more additives. Examples of particularly useful additives include a diluent and a lubricant to aid flow of the active ingredient during manufacture. The diluent may be, for example, lactose. The lubricant may be for example, magnesium stearate and /or talcum. It will be appreciated that the pharmaceutical compositions of the invention may contain any one or more other additives conventionally used in the formulation of pharmaceutical compositions. The excipients known in the art of manufacturing these dosage forms include lactose, microcrystalline cellulose, dicalcium phosphate, HPC, L-klucel, HPMC starch, sugar, disintegrants such as starch and derivatives of starch, crosscarmellose sodium, sodium carboxy methyl cellulose and its derivatives, crospovidone, etc. The pharmaceutical composition as per the present invention may take the form of tablets or peltabs or pellets in a capsule. According to a first embodiment of the present invention, the bisphosphonic acid or salt thereof is present in the core. Suitably, the core of the pharmaceutical composition comprises a plurality of compressed granules of the bisphosphonic acid. This embodiment is particularly useful when it is desired to provide the pharmaceutical composition in tablet form. There is further provided by the present invention a tablet which comprises a pharmaceutical composition substantially as herein described, wherein the core is formed from a plurality of granules comprising the bisphosphonic acid, which granules are compressed together to form the core. According to this embodiment of the present invention, the seal is applied around the active core, then the enteric coating is suitably provided around the seal coated active core. According to a second embodiment of the present invention, the bisphosphonic acid or salt thereof is present in the active core. The second embodiment of the present invention is particularly applicable for the inclusion of a plurality of pellets in a capsule. An active cores of the pellets may comprise non - pareils provided in the form of sugar beads or sugar/starch beads on to which bisphosphonic acid or salt thereof is loaded. When the pellets comprise bisphosphonic acid or salt thereof loaded onto a plurality of inert cores suitable for inclusion in a capsule, the bisphosphonic acid or salt thereof together with or without additives can be sprayed on to the inert core. For example the bisphosphonic acid or salt thereof may be mixed with one or more additives before being loaded on the inert cores. As described above, the additives may include, for example, a solubiliser and / or a lubricant. The inert cores can be loaded with the bisphosphonic acid (together with any additives) , and sprayed with a binder, in a centrifugal coating apparatus. According to the above embodiment of the present invention, the seal coating Is applied around the active core of each of the pellets to be provided in a capsule, and the enteric coating is suitably provided around the seal coating on each of the active cores. According to this embodiment of the present invention there is therefore provided a capsule which comprises a capsule shell containing a plurality of pellets. According to third embodiment of the present invention, bisphosphonic acid or salt thereof is present in the active core. The third embodiment of the present invention is particularly applicable for the compression of a plurality of pellets in a tablet form. The active cores of the pellets may comprise non pareils provided in the form of sugar beads or sugar/starch beads on to which bisphosphonic acid or salts thereof is loaded. According to the third embodiment of the present invention, the seal coating is applied around the active core of each of the pellets, and the enteric coating is applied around the active core of each pellets, and the enteric coating is suitably provided around the seal coating on each of the active cores. These plurality of pellets together with conventional excipients such as disintegrants and binders are compressed into tablets, generally known as peltabs. The following general and specific examples illustrate the invention. In each case, the active drug was bisphosphonic acid or salt thereof unless indicated othenwise. Whilst sucrose (sugar) is the illustrated binding agent, other binding agents such as polyvinylpyrrolidone, shellac or xanthan gum, may be used instead. General Examples: Example 1 Pellets: A plurality of particles containing the active drug are prepared from the following materials: Non-pareil seeds 95mg Active drug 13.03mg Sucrose 31.97mg Corn Starch 32mg Talcum 10mg HPMC 1mg 183mg Water: as required Seal Coating : HPMC 7.2mg Talc 1.4mg Propylene glycol 1.4mg 10mg Water: as required. Isopropyl alcohol: as required Enteric Coating : Eudragit L100-55 22.50mg Sodium hydroxide 0.320mg Triethyl citrate 2.270mg Talc 22.50mg Titanium dioxide 2.18mg Aerosil 0.23mg 50.00mg Water; as required. Initially, the active drug, the sucrose, the corn starch and the talcum are blended thoroughly to yield a dusting powder. The non-pareil seeds are loaded into a centrifugal coater and then coated with the dusting powder while spraying the HPMC (hydroxypropyl methyl cellulose) solution. This results in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained are dried using conventional tray dryers/fluids bed dryers to an outlet temperature of 45°C. These particles are then seal coated using HPMC solution and further enteric coated in suitable Wurster coater. Example 2 Pellets: A plurality of particles containing the active drug are prepared as follows: Non - Pareil seeds 95mg Active drug 13.03mg Sucrose 31.97mg Talcum 10mg HPMC 1mg 183mg Water: as required. Seal coating: HPMC 7.2mg Talc 1.4mg Propylene glycol 1.4mg 10mg Water: as required Isopropyl alcohol: as required. Enteric coating: Eudragit L 100-55 18.00mg Sodium hydroxide 0.25mg Triethyl citrate 1.81mg Talc 18.00mg titanium dioxide 1.75mg Aerosil 0.19mg 40.00mg Water: as required Initially, the active drug, the sucrose, the corn starch and the talcum are blended thoroughly to yield a dusting powder. The non-pareil seeds are loaded into the centrifugal coater and then coated with the dusting powder while spraying the HPMC (hydroxypropyl methyl cellulose) solution. This results in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained are dried using conventional tray dryers/fluids bed dryers to an outlet temperature of 45°C. These particles are then seal coated using HPMC solution and further coated in suitable Wurster coater. Example 3 Peltabs: A plurality of particles containing the active drug are prepared from the following materials: Non-pareil Seeds 110.07mg Active drug 13.03mg Sucrose 35.90mg Cornstarch 21.00mg Talcum 2mg HPC-LKIucel Img 183mg Water: as required. Seal coating: HPMC 7.2mg Talc 1.4mg Propylene glycol 1.4mg 10mg Water: as required Isopropyl alcohol: as required. Enteric coating: Eudragit L 100-55 22.50mg Sodium Hydroxide 0.32mg Triethyl citrate 2.270mg Talc 22.50mg Titanium dioxide 2.18mg Aerosil 0.23mg 50.00mg Water: as required. Microcrystalline cellulose 50mg Croscarmellose sodium 7mg 57.00mg Initially, the active drug, the sucrose, the corn starch and the talcum are blended thoroughly to yield a dusting powder. The non-pareil seeds are loaded into the centrifugal coater and then coated with the dusting powder while spraying the HPC-L-Klucel (hydroxypropyl cellulose) solution. This results in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained are dried using conventional tray dryers/fluid bed dryers to an outlet temperature of 45°C. These particles are then seal coated using HPMC solution and further enteric coated in suitable Wurster coater. This is then suitably diluted with binders and disintegrants, and compressed by conventional means. Specific examples: Example 4 Tablets: Tablet cores containing an active drug are prepared from the following materials: Alendronate sodium trihydrate 13.03mg Lactose 127.97mg Microcrystalline cellulose (MCC) 103.00mg Croscarmellose Na 3.00mg Magnesium stearate 3.00mg 250.00mg Seal Coating : HPMC 5.76mg Talc 1.12mg Propylene glycol 1.12mg S.OOmg Enteric coating: Eudragit L 100-55 Sodium hydroxide Triethyl citrate Talc Titanium dioxide Aerosil 6.750mg 0.095mg 0.680mg 6.750mg 0.655mg 0.070mg 15.00mg Water: as required Initially the active drug is blended with the MCC, lactose and croscarmellose sodium in a suitable mixer. The blend containing the active drug is lubricated with magnesium stearate. Finally, the blend is compressed into a suitable shape for a tablet core using conventional compression equipment. The resulting tablet core is then coated using HPMC solution. These seal coated tablets are then enteric coated. Example 5 Tablets Tablet cores containing an active drug are prepared from the following materials Alendronate sodium trihydrate Lactose Microcrystalline Cellulose (MCC) Croscarmellose Na Magnesium stearate Seal coating : HPMC Talc Propylene glycol Enteric coating : Eudragit L100-55 Sodium hydroxide Triethyl citrate Talc Titanium dioxide 0.436mg Aerosil 0.045mg lO.OOmg Water: as required. Initially the active drug is blended with the MCC, lactose and croscarmellose sodium in a suitable mixer. The blend containing the active drug is lubricated with magnesium stearate. Finally, the blend is compressed into a suitable shape for a tablet core using conventional compression equipement. The resulting tablet core is then coated using HPMC solution. These seal coated tablets are then enteric coated. WE CLAIM 1. A process for preparing a pharmaceutical composition comprising the steps of: providing an inert core, applying an active coating over said inert core to form an active core, applying a seal coating over said active core, and applying an enteric coating around the seal coating to form pellet; wherein the active coating comprises 5.36% by weight of at least one bisphosphonic acid or salt thereof such as alendronate sodium trihydrate, etidronate, clodronate, pamidronate, or ibandronate . 2, A process for preparing pharmaceutical composition as claimed in claim 1, wherein the atleast one bisphosphonic acid is selected from the group consisting of: 4 -Amino - 1 hydroxybutyiidene ~ 1,1-bisphosphonic acid; N- Methyl - 4 - amino-1-hydroxybutyiidene -1,1- bisphosphonic acid; 4-(N,N-dimethyiamino)-1-hydroxybutyiidene - 1, 1- bisphosphonic acid; 3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid 3-(N,N-Dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid; 1-Hydroxy-3-(N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid 1-hydroxy - 2- [3-pyridinyl] ethylidene-1, 1-bisphosphonic acid 4- (Hydroxymethylene -1, 1- bisphosphonic acid) - piperidine; and salt thereof. 3. The process according to claim 1, wherein the seal coating is selected from the group consisting of polyvinyl-pyrrolidone, shellac, xanthan gums, hydroxypropyl methylcellulose, hydroxypropyl cellulose , cellulose gums. 4. The process as claimed in claim 1, wherein the enteric coating is selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetyl succinate, cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid-methyl methacrylate copolymers and mixtures thereof. 5. A process for preparing a pharmaceutical composition as claimed in claim 1 wherein a composition is in the form of pellets in a capsule or peltabs. Dated this 20th day of October, 1999. FOR CIPLA LIMTED (By Their Agent) UMA BASKARAN (KRISHNA & SAURASTRI)

Documents:

709-bom-1999-cancelled pages(28-11-2005).pdf

709-bom-1999-claim(granted)-(28-11-2005).doc

709-bom-1999-claims(granted)-(28-11-2005).pdf

709-bom-1999-correspondence(28-11-2005).pdf

709-bom-1999-correspondence(ipo)-(17-06-2008).pdf

709-bom-1999-form 1(03-11-1999).pdf

709-bom-1999-form 1(20-10-1999).pdf

709-bom-1999-form 13(28-11-2005).pdf

709-bom-1999-form 19(17-10-2003).pdf

709-bom-1999-form 2(granted)-(28-11-2005).pdf

709-bom-1999-form 3(07-10-2005).pdf

709-bom-1999-form 4(26-10-2005).pdf

709-bom-1999-form 5(03-11-1999).pdf

709-bom-1999-form 5(20-10-1999).pdf

709-bom-1999-from 2(granted)-(28-11-2005).doc

709-bom-1999-petition under rule 137(07-10-2005).pdf

709-bom-1999-power of authority(03-11-1999).pdf