WO2010112965A1

WO2010112965A1 - Isolation coating of diclofenac tablets

Info

Publication number: WO2010112965A1
Application number: PCT/IB2009/051322
Authority: WO
Inventors: Farhad Farshi; Levent KANDEMİR; Zerrin Ozge Samuk; Serdar Soylemez; Fikret Koc
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Current assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Priority date: 2009-03-30
Filing date: 2009-03-30
Publication date: 2010-10-07
Anticipated expiration: 2011-09-30

Abstract

This invention is related to a isolation coating of diclofenac comprising a glycerol ester of fatty acid or mixtures thereof and an agent selected from group consisting of ethyl cellulose, car- boxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar, povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose,hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin, methyl- cellulose,shellac,polyvinyl acetate phthalate or mixtures thereof.

Description

Title of Invention: ISOLATION COATING OF DICLOFENAC

TABLETS

[1] This invention is related to using of combination of a glycerol ester of fatty acid or mixtures thereof and an agent selected from group consisting of ethyl cellulose, car- boxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar , povidone, copovidone, gelatin,cellulose acetate, cellulose acetate phthalate, hypromellose,hypromellose acetate succinate, hypromellose phthalate,hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac,polyvinyl acetate phthalate or mixtures thereof in coating of diclofenac tablet core.

[2] In US 6,692,769 patent, it is disclosed that using of glycerin esters of higher fatty acids, such as stearin, myristin, palmitin and laurin etc, which are used in coating of sustained release particles (column 2, lines 5-30) . This invention is different from US 6,692,769 because in this invention there is no coating of particles provides sustained release and glycerol esters of fatty acids are used in combination with an agent selected from a group, which is pointed out below.

[3] EP 383967 delineates a pelleted oral diclofenac preparation with a prolonged action and an improved shell resistant to gastric juice by preparation consisting partly of quick-release diclofenac and partly of pellets with a shell resistant to gastric juice. The shell is made up of 100 parts of methaacrylic acid/methyl methacrylate copolymer, 3-40 parts of glycerol fatty acid ester and 1-150 parts of talc. This invention is different from EP 383967 since according to this invention sugar coated tablet is not long acting tablet and glycerol fatty acid ester should be used in combination with an agent selected from a group, which is pointed out below, to obtain of similarity of test product when compared with reference product . The release of tablet dissolution rate decreases dramatically with the increase of Methaacrylic acid/methyl methacrylate copolymers since they are strong sustaining agent. Thus the using range of methacrylic acid/methyl methacrylate copolymers is narrow and it does not properly persuade to be formulated for suitable dissolution rates .

[4] Diclofenac is an effective analgesic, anti-pyretic, anti-phlogistic, antirheumatic and anti- arthritic non-steroidal anti-inflammatory drug (NSAID). It is available, as diclofenac sodium, and also diclofenac potassium as sugar coated tablets along with other pharmaceutical administration forms .

[5] Voltarol ® Rapid includes diclofenac potassium which is on the market as a reference drug.

[6] Technical problem is that thoroughly adjusting of in vitro dissolution profile in pH 7.5, pH 6, pH 8 and other suitable environments to reach desired dissolution profile of test product in comparison with reference product . It is invented that in case of using glycerol esters of fatty acids in combination with an agent selected from group consisting of ethyl cellulose, carboxymethylcellulose sodium, chitosan hydrochloride, carrageenan,alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac, polyvinyl acetate phthalate or mixtures thereof in coating of tablet core , preferably ethyl cellulose, in a specific range by weight desired dissolution profiles are obtained comparatively with reference product in said environments .

[7] Thus, the present invention concerns a sugar coated tablet comprising (i) a tablet core including diclofenac or a pharmaceutically acceptable salt thereof and suitable pharmaceutical excipient or excipients, and (ii) at least one isolation coating comprising a glycerol ester of fatty acid or mixtures thereof and an agent selected from group consisting of ethyl cellulose , carboxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac, polyvinyl acetate phthalate or mixtures thereof. Said combination in (ii) is used in isolation coating.

[8] In another aspect, this invention is related to combination of glycerol esters of fatty acids and an agent selected from group consisting of ethyl cellulose carboxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac,polyvinyl acetate phthalate or mixtures thereof in coating of diclofenac or a pharmaceutically acceptable salt thereof. It embraces all of the compressed dosage form including tablet or sugar coated tablet (dragee). According to this invention preferred embodiment of compressed dosage form is sugar coated tablet (dragee).

[9] Diclofenac may be in the form of free acid or pharmaceutically acceptable salts thereof such as, but not limited, diclofenac sodium, diclofenac potassium etc. In this invention, diclofenac potassium is particularly preferred.

[10] Glycerol fatty acids and their derivatives may be used. Glycerol esters of fatty acids are, but not limited to, glycerol fatty acid ester, glycerol acetic acid fatty acid ester, glycerol lactic acid fatty acid ester, glycerol citric acid fatty acid ester, glycerol succinic acid fatty acid ester, glycerol diacetyl tartaric acid fatty acid ester, glycerol acetic acid ester or whatsoever. [11] Glycerol esters of fatty acids, for example, but not limited, may be glycerol oleate, glycerol monostearate, glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glyceryl caprylate/caprate, glycerol linoleate, glyceryl lauropalmitooleate etc. In coating, mixtures of glycerol esters of fatty acids may also be used. In this invention glycerol oleate is preferred. Glycerol ester of fatty acid or mixtures of glycerol esters of fatty acids is/are usedin the range of 0.1-90 % by weight of total isolation coating. In calculation, if there is, evaporated agents used in isolation coating are ruled out.In isolation coating of tablet core, aglycerol ester of fatty acid or mixtures of glycerol esters of fatty acids is/are used in combination with an agent selected from group consistingof ethyl cellulose, carboxymethylcellulose sodium, chitosan hydrochloride, carrageenan,alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac, polyvinyl acetate phthalate. An agent or mixtures of agents from the said group is/are used in the range of 0.1-90 % by weight of total isolation coating. In calculation, if there is, evaporated agents using in isolation coating are ruled out.

[12] Generally, glycerol oleate can be used to sustain the release of various water soluble drugs. On the other hand, in formulations, ethylcellulose is used to modify the release of a drug as a coating agent. However in this invention both glycerol oleate and ethyl- cellulose are used so as to provideimmediate release tablet formulation. Diclcofenac potassium is a water soluble drug.

[13] Without combination with said agent or agents above, if a glycerol ester of fatty acid or mixtures thereof is/are used alone in isolation coating of diclofenac ,desired dissolution profile is not obtained since glycerol ester of fatty acid or mixtures thereof is/ are rapidly dissolved in different dissolution mediums when compared to reference tablet. (Figure 1) . In this invention glycerol oleate is employed as glycerol ester of fatty acid . Experiment disclosed in figure 1 is carried out under conditions of dissolution method ; USP, Metot II - Pedal, dissolution environment ; pH 7.5, temperature ; 37⁰C, dissolution volume ; 900 ml, dissolution speed ; 50 rpm . Similarly, without combination of glycerol ester of fatty acid or mixtures thereof preferably glycerol oleate and an agent preferably ethyl cellulose,desired dissolution profile is not obtained since coating is rapidly dissolved in different solution mediums when compared to reference tablet (Figure 2). Experiment disclosed in figure 2 is carried out under conditions of dissolution method ; USP- Metot II - Pedal, dissolution environment ; pH 7.5, temperature ; 37⁰C, dissolution volume ; 900 ml, dissolution speed ; 50 rpm . If glycerol oleate and ethyl cellulose is used as a combination in isolation coating, dissolution curves of test tablets and reference tablets are overlapped in pH 7.5 medium (Figure 3). Experiment disclosed in figure 3 is carried out under conditions of dis- solution method ; USP- Metot II - Pedal, temperature ; 37⁰C, dissolution volume ; 900 ml, dissolution speed ; 50 rpm .

[14] Coating may contain further suitable excipients such as, but not limited, micro- crystalline cellulose,hydroxypropylmethylcellulose, polyethylene glycol, iron oxide, polyvinylpyrrolidone, talc, sugar, deionized water (evaporated in final coating) , ethyl alcohol (evaporated in final coating) .

[15] In yet another aspect of this invention is preparation method of coating . Coating has four steps as (i) isolation coating, (ii) talc coating, (iii)sugar coating and (iv) polishing.

[16] (i) The tiers of first step's (isolation coating) are : a. Dissolving ethylcellulose in ethyl alcohol, b. Adding HPMC and mixing until it dissolves, c. Adding Oleate Glycerol and then mixing, d. Coating of tablets.

[17] (ii) The tiers of second step's(talc coating) are : a. Taking deionized water in a solution preparation tank and heating, b. Adding and dissolving sugar ,c. Adding and mixing PEG and Polyvinylpyrrolidone, d. Adding and mixing microcrystalline cellulose and Talc, e. Adding and mixing red iron oxide, f. Coating of isolation coated tablet

[18] (ii) The tiers of third step's (sugar coating) are : a. Taking deionized water ,b. Adding and mixing sugar until it dissolves,c. Adding and mixing red iron oxide,d. Coating of talc coated tablet.

[19] (iii)The tiers of fourth step's (polishing) are : a. adding and dissolving sugar, b.

Adding and mixing PEG, c. spraying of polishing solution on to the sugar coated tablets.

[20] Dissolution profiles of reference tablets and test tablets should be same or identical in different dissolution mediums. Desired dissolution profile means that in targeted dissolution mediums f2 value should be at least 50 to 100 when compared to the reference dissolution profile. The similarity factor f2 is a measurement of the similarity through a point by point comparison as shown in equation 1.

[21] Equation 1

[22] n: is the number of sampling time points

[23] R : is the amount drug released from a reference batch at time t

[24] Tt : is the amount drug released from a test batch at time t.

[25] Generally, if f2 values are greater than 50, it ensures sameness of the performance of the reference product and test product so as to obtain bioequivalance.

[26] Put another way ,the aim of this invention is to obtain a tablet core formulation. The tablet core formulation can include suitable excipients , but are not limited to, lubricants, diluents, binders, fillers, disintegrants and the like which might be needed for the preparation of tablet core formulation.

[27] Fillers are selected from the group consisting of, but not limited to, lactose, micro- crystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch or mixtures thereof. Preferred filler is microcrystalline cellulose.

[28] Lubricants used in the tablet core according to the present invention may be selected from the group consisting of, but not limited to, magnesium stearate, magnesium lauryl sulphate,sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof. Preferred lubricant is magnesium stearate.

[29] Disintegrants are selected from the group consisting of, but not limited to, modified starches, croscarmallose sodium, carboxymethylcellulose calcium, sodium starch glycolate ,crospovidone or mixtures thereof. Preferred disintegrant is sodium starch glycolate.

[30] Binders are selected from the group consisting of, but not limited to starch, polyvinylpyrrolidone, sodium alginate, ethylcellulose, pregelatinized starch, gelatin or mixtures thereof. Preferred binder is polyvinylpyrrolidone .

[31] Diluents are selected from the group consisting of, but not limited to, starches,maizestarch, potato starch, rice starch, wheat starch, pregelatinized starch,starch 1500, , fully pregelatinized starch , lactose, mannitol , cellulose derivatives, confectioner's sugar or mixtures thereof. Preferred diluent is maize starch.

[32] Example 1 [Table 1] [Table ]

[33] Example 2

[Table 2] [Table ]

Claims

[Claim 1] An immediate release tablet formulation of diclofenac or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient or excipients, having desired dissolution profile, comprising;

(a) a tablet core and

(b) isolation coating characterized in that said isolation coating comprises in combination of ;

(i) A glycerol ester of fatty acids or mixtures of glycerol esters of fatty acids and

(ii) An agent selected from group consisting of ethyl cellulose, car- boxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac,polyvinyl acetate phthalate or mixtures thereof

[Claim 2] As claimed in claim 1, A glycerol ester of fatty acids or mixtures of glycerol esters of fatty acids is/are used in the range of 0.1-90 % by weight of total isolation coating.

[Claim 3] As claimed in claim 1, an agent selected from group consisting of ethyl cellulose, carboxymethylcellulose sodium, chitosan hydrochloride, carrageenan, alginic acid, agar , povidone, copovidone, gelatin, cellulose acetate, cellulose acetate phthalate, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose,maltodextrin,methylcellulose,shellac,polyvinyl acetate phthalate or mixtures thereof is/are used in the range of 0.1-90 % by weight of total isolation coating.

[Claim 4] As claimed in claim 1, desired dissolution profile exhibits a similarity factor (f2) of at least 50 to 100 in dissolution environments when compared to the reference (Voltarol ® Rapid) dissolution profile.

[Claim 5] As claimed in claim 4, dissolution environments are pH 7.5, pH 6 and pH8.

[Claim 6] As claimed in claim 1, tablet core comprising lubricants, diluents, binders, fillers, disintegrants.

[Claim 7] As claimed in cliam 6, lubricants are selected from the group consisting of magnesium stearate, magnesium lauryl sulphate,sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof.

[Claim 8] As claimed in claim 7, lubricant is magnesium stearate.

[Claim 9] As claimed in claim 6, diluents are selected from the group consisting of starches,maizestarch, potato starch, rice starch, wheat starch, prege- latinized starch,starch 1500, fully pregelatinized starch , lactose, mannitol , cellulose derivatives, confectioner's sugar or mixtures thereof.

[Claim 10] As claimed in claim 9, diluent is maize starch.

[Claim 11] As claimed in cliam 6, binders are selected from the group consisting of starch, polyvinylpyrrolidone, sodium alginate, ethylcellulose, pregelatinized starch, gelatin or mixtures thereof.

[Claim 12] As claimed in claim 11, binder is polyvinylpyrrolidone .

[Claim 13] As claimed in claim 6, fillers are selected from the group consisting of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch or mixtures thereof.

[Claim 14] As claimed in claim 13, filler is microcrystalline cellulose.

[Claim 15] As claimed in claim 6, disintegrants are selected from the group consisting of modified starches, croscarmallose sodium, car- boxymethylcellulose calcium, sodium starch glycolate ,crospovidone or mixtures thereof.

[Claim 16] As claimed in claim 15, disintegrant is sodium starch glycolate.

[Claim 17] As claimed in claim 1, diclofenac is diclofenac potassium.

[Claim 18] As claimed in claim 1, agent is ethyl cellulose.

[Claim 19] As claimed in claim 1, glycerol esters of fatty acids are glycerol oleate, glycerol monostearate, glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glyceryl caprylate/caprate, glycerol linoleate, glyceryl lauropalmitooleate.

[Claim 20] As claimed in claim 19, glycerol ester of fatty acid is glycerol oleate.

[Claim 21] As claimed in claim 1, coating comprises further excipients as micro- crystalline cellulose,hydroxypropylmethylcellulose, polyethylene glycol, iron oxide, polyvinylpyrrolidone, talc, sugar, deionized water and ethyl alcohol .

[Claim 22] As claimed in claim 1, isolation coating further comprises hy- droxypropyl methylcellulose

[Claim 23] As claimed in claim 1, tablet is sugar coated tablet.

[Claim 24] A preparation method of coating comprises steps of ;

(i) isolation coating and,

(ii) talc coating and,

(iii) sugar coating and,

(iiii) polishing.

[Claim 25] As claimed in claim 23, isolation coating step comprises tiers of a. Dissolving ethylcellulose in ethyl alcohol and, b. Adding HPMC and mixing until it dissolves and, c. Adding Oleate Glycerol and then mixing and, d. Coating of tablets.

[Claim 26] As claimed in claim 24, talc coating step comprises tiers of a. Taking deionized water in a solution preparation tank and heating and, b. Adding and dissolving sugar and , c. Adding and mixing PEG and Polyvinylpyrrolidone and, d. Adding and mixing microcrystalline cellulose and talc and, e. Adding and mixing red iron oxide and f. Coating of isolation coated tablet

[Claim 27] As claimed in claim 24, sugar coating step comprises tiers of a. Taking deionized water and, b. Adding and mixing sugar until it dissolves and, c. Adding and mixing red iron oxide and d. Coating of talc coated tablet.

[Claim 28] As claimed in claim 24, polishing step comprises tiers of a. Adding and dissolving sugar and, b. Adding and mixing PEG and , c. Spraying of polishing solution on to the sugar coated tablets.

[Claim 29] According to claim 1, glycerol esters of fatty acids are glycerol fatty acid ester, glycerol acetic acid fatty acid ester, glycerol lactic acid fatty acid ester, glycerol citric acid fatty acid ester, glycerol succinic acid fatty acid ester, glycerol diacetyl tartaric acid fatty acid ester, glycerol acetic acid ester or mixtures thereof.