SK63098A3 - Controlled-release pharmaceutical formulation, process for its preparation and use of polyethyleneoxide - Google Patents

Abstract

The invention provides a controlled-release pharmaceutical formulation for oral administration consisting essentially of: an active drug compound; low molecular weight polyethylene oxide; hydroxypropylmethyl cellulose; tabletting excipients; and optionally one or more enteric polymers. Formulations according to the invention produce a constant rate of release of drug in in vitro models of the gastrointestinal tract.

Description

Controlled release pharmaceutical composition, process for its manufacture and use of polyethylene oxide

Technical field

The present invention relates to a controlled release oral pharmaceutical composition, to a process for its manufacture and to the use of low molecular weight polyethylene oxide in the composition.

The art is well known in the art

Oral controlled-release pharmaceutical compositions are known. The purpose of such means is to modify the release rate of lleClva, for example, to achieve a constant release rate of lleClva into the patient ' s intrinsic tract, or to delay release into the patient ' s intrinsic tract. 3-6, edited by J. R. Roblnson, edited by Flarcel Dekker Inc.).

U.S. Pat. No. 4,765,989 discloses an osmotic delivery device in addition to other or doxazosin. The device has a perforated semipermeable wall surrounding a pharmaceutical composition comprising an osmopolymer and a printing composition comprising a second osmopolymer. The functional efficiency of this prior art device is satisfactory; Its disadvantage is that it is very complicated what leads to high production costs.

GB patent application 2 123 291 discloses a sustained release formulation of sucrose. which consists of a two-part tablet, the first part of which is an immediate release portion and the second part is a slow-release portion, wherein the tablet must contain a surfactant to increase bloerusion.

U.S. Patent No. 5,393,765 discloses an erodible zero-order pharmaceutical composition, hydroxypropylmethylcellulose.

providing a managed profile which contains a low-profile

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a controlled release pharmaceutical composition for oral administration consisting essentially of the active compound: low molecular weight polyethylene oxide; hydroxypropylmethylcelluloses of tabletting exclplents; and optionally at least one enteric polymer.

The description of FIG. in the drawings

In FIG. 1 shows the release of the drug compound versus time (CX) from the compositions of the invention (prepared according to Examples 1Ca) and 1Cb)) as compared to the control composition (prepared according to Example 6) using a simple dissolution test.

In FIG. 2 shows the release of the drug compound as a function of time C X) from the composition of the invention C prepared according to Example 2a) in the dissolution test using an acidic and then neutral dissolution medium first.

Oral administration means in the mouth and then swallowed. Compositions of the Invention However, it is also possible to administer buccally (i.e., place the composition behind the upper pen and allow it to dissolve).

I

By substantially composed is meant that at least 95% by weight of the composition is comprised of said components. The uncoated compositions and the cores of the coated compositions are preferably at least 99% by weight of said components.

Polyethylene oxide having a number average molecular weight of less than 100,000 is sometimes referred to as polyethylene glycol. For the sake of simplicity, however, the term low molecular weight polyethylene oxide is used to denote a number average molecular weight polymer having a number average molecular weight of from 15,000 to 750,000.

Tableting excipients in the compositions of the invention may be conventional tabletting excipients, for example, calcium phosphate, lactose and magnesium stearate.

For administration in the compositions of the present invention, three triglycerol compounds are suitable. The first class are weak basic compounds. Examples of compounds of this class include dlpyridamol, noscapine, papaverine, doxazosin, sildenafil and prazosin. Of great interest in this regard is doxazosin and its pharmaceutically acceptable salts.

The second class are compounds with high solubility in aqueous media. Examples of compounds of this class include salbutamol, metoprolol, propanolol, amlnophyllin, isosorbide mono- and dl-filtrate, glyceryl tri-filtrate, verapamil, captopril, morphine, chlorphenlramine, promethazine, eletrliptane, darlphenol, darlphenol, darlofenol.

The third class includes compounds having low solubility in aqueous media. Examples of such compounds include nflfllll, grlseofullll, carbamazepll, felodllll, nlmodlll and megestrol.

The terms high solubility in aqueous media and low solubility in aqueous media will be well understood by those skilled in the art. However, the first can be defined as the solubility of > 1 mg / ml water and the second as the solubility < 1 mg / ml water.

Those skilled in the art will recognize that some compounds may belong to more than one of the above classes. For example, certain compounds may be weakly basic and exhibit high solubility in aqueous media.

The compositions of the invention are advantageous in that they achieve a constant rate of drug release that is poorly alkaline and / or highly soluble in aqueous media in the low gastronestinal tract models and can therefore be expected to achieve a constant rate of use.

I release the drug in the gastrointestinal tract of the patient. When the drug to be administered exhibits low solubility in aqueous media, the advantage of the composition according to the invention is that it allows for delayed or pulsed drug release. Nevertheless, such compositions are very simple and can be manufactured at relatively low cost.

The preferred is the hydroxypropyl number average molecular weight of 90,000 to 250 000. The degree of the hydroxypropyl preferably has a methyl substitution in the range of 19 to 30 X. The degree of hydroxyl substitution of hydroxypropyl methylcellulose is preferably in the range of 4 to 12, X is marketed under the trade ľlethocel ^R * * The available amounts of hydroxypropylmethylcellulose polymers and some of them that are suitable for the compositions of the invention are listed in the following table.

Chestnut * ^R * species Numeric mol. materials. Degree of methyl substitution (X) Degree of hydroxyl substitution (X) Nominal viscosity of 2X solution in water (mPa.s) Marking according to llekopls USP Κ4Π 99 000 19 to 24 4 to 12 4 000 2209 K15N 125 000 - - 15 000 - Κ100ΙΊ 215 000 - - 100000 - E4N 93 000 29 to 30 7 to 12 4 000 2910 Ε10Γ1 113 000 - - 10 000 - F4FI 90 000 27 to 30 4 to 7, 5 4 000 2906

Methocel® ^R 'K4H has very advantageous properties.

Low molecular weight polyethylene oxide preferably has a number average molecular weight in the range of from 20,000 to 500,000, more preferably from 100,000 to 300,000. Polyethylene oxide with a number average molecular weight of more than 100,000 is a powder that is easier to handle than lower polyethylene oxide. molecular weight having a lower melting point. For example, polyethylene oxide having a number average molecular weight of 6000 has a melting point of 60-63 ° C.

It will be apparent to those skilled in the art that polyethylene oxide may consist of molecules with different chain lengths, but that the average chain length will correspond to the molecular weight within the stated range. This also applies to hydroxypropylmethylcellulose.

The compositions of the invention may comprise an enteric polymer admixed with the other ingredients of the composition. Additionally or alternatively, the compositions of the invention are preferably coated with an enteric polymer. Suitable enteric polymers include phthalate derivatives (including cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropylmethylcellulose phthalate), polyacrylic acid derivatives (including methacrylic acid copolymer), and a copolymer of wool acetate and crotonic acid. A very interesting is the methacrylic acid copolymer.

In a preferred embodiment, the composition comprises up to 50, for example 1 to 20, by weight of the active HeCl 2 compound.

The compositions according to the invention preferably contain 5 to 30, for example 6 to 10,% by weight of low molecular weight polyethylene oxide.

The compositions according to the invention preferably contain 10 to 60, for example 25 to 35,% by weight of hydroxypropyl methylcellulose.

In compositions comprising an enteric polymer admixed with the other ingredients of the composition, the admixed enteric polymer preferably comprises 10 to 40%, for example 25 to 30% by weight.

In the compositions of the invention, the weight ratio of low molecular weight polyethylene oxide to hydroxypropyl methylcellulose is preferably from 2 to 1 to 5.

I

In compositions according to the invention comprising an admixed enteric polymer, the weight polymer is a (low molecular weight polyethylene oxide + hydroxypropylmethylcellulose) admixed enteric polymer preferably in the range of from 1 to 2 to 6, preferably from 1 to 2 to 1. The enteric coating, if present, constitutes 2 to 15, more preferably 5 to 10, by weight of the composition.

In another aspect, the present invention provides the use of low molecular weight polyethylene oxide in controlled release oral pharmaceutical compositions having a hydroxypropylmethylcellulose matrix to enhance matrix erosion after a predetermined period of time after administration of the composition to a patient. Such a predetermined time is, for example, 6 hours. In this way, it is possible to achieve a constant rate of drug release in the gastrointestinal tract of the patient despite varying conditions along the gastrointestinal tract.

By varying the proportion of polyethylene oxide in the composition, it is possible to control the onset of enhanced matrix erosion, i.e., the onset of enhanced drug release upon administration of the composition to a patient.

In yet another aspect, the present invention provides a process for the preparation of the above-defined pharmaceutical composition, wherein the active drug compound is mixed; low molecular weight polyethylene oxide; hydroxypropyl methylcellulose; tabletovacle exclplenty; and optionally at least one enteric polymer; and the resulting mixture is then compressed into tablets.

The selectivity of the compositions of the invention can be determined on a model of the gastrointestinal tract, such as Device 1 described in USP 22, page 1578, by Method 1.

With cupcakes).

The invention is illustrated in more detail in the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Sustained release formulations of doxazosin methanesulfonate

ca)

Ingredient mg / tablet

Doxazosin methanesulfonate * 3, 636

Polyethylene oxide with molecular weight

100,000 ^p 9, 000

Polyethylene oxide with molecular weight

200,000 ^c 9, 000 Hydroxypropylmethylcellulose ^d 60,000 Dibasic calcium phosphate * 58,182 lactose * 58,182 Top Stearate 2, 000 Overall 200,000

* equivalent of 3 mg doxazosin, based on theoretical efficacy

82.5% as Polyox ^tR * USR N 10 ^e as Polyox ^CR> USR N 80 ^d as Methocel ^tR> <41 * 1 * as anhydrous * as fast flo lactate θ

All ingredients except magnesium stearate are mixed together in a Turbula mixer for 10 minutes. The resulting mixture was sieved using a 500 µm sieve and stirring was continued for a further 10 minutes. The magnesium stearate is passed through a 500 µm sieve and added to the preformed mixture. The mixture is stirred for an additional 5 minutes and subjected to compression in a tabletting machine using an 8mm normal round convex punch. This gives the desired number of 200 mg tablets.

C b)

component mg / tablet Doxazosin methanesulfonate * 4. 876

Polyethylene oxide with molecular weight

100,000 ^p 20. 000

Polyethylene oxide with molecular weight

200,000 ^c 20. 000 Hydroxypropylmethylcellulose ^d 60. 000 Calcium phosphate * 46.562. lactose * 46. 562 Top Stearate 2. 000 Overall 200. 000 * equivalent of 4 mg doxazosin. related to theoretical efficiency

82.5 X ^b as Polyox ^<R> USR N 10 ^c as Polyox ^<R> WSR N 80 ^- as Methocel * ^R * K4I * I • as anhydrous * as lactose fast flo

200 mg tablets are prepared as described in Part C a).

C (c)

component mg / tablet Doxazosin methanesulfonate * 4, 876 Polyethylene oxide with molecular weight 100000" 30,000 Polyethylene oxide with molecular weight 200,000 * = 30,000 Hydroxypropylmethylcellulose ^d 60,000 Calcium phosphate * 36, 562 lactose * 36, 562 Magnesium stearate 2, 000 Overall 200,000 * equivalent of 4 mg doxazosin based on theoretical efficacy 82,5 X ^b as Polyox ^{t R} 'USR N 10 ^e as Polyox ^<R> USR N 80 ^d as Methocel ^{® R} 'K4M * as anhydrous * as lactdza fast flo The procedure described in (a) shall: prepare 200mg tablets. Example 2 Sustained release formulations of doxazosin methanesulfonate containing enteric polymer ca) component mg / tablet

Doxazosin methanesulfonate * 3, 636 Polyethylene oxide with molecular weight weight 100,000 ^p 9, 000

Polyethylene oxide with molecular weight

200,000 ^e 9, 000 Hydroxypropylmethylcellulose ^d 6.0, 000 C-methacrylic acid copolymer * Dibasic calcium phosphate * 60,000 28,182 Laktúza 28,182 Magnesium stearate 2, 000 Overall 200,000

* equivalent of 3 mg doxazosin based on theoretical efficacy

82.5 X ^h as Polyox ^<R> USR N 10 ^e as Polyox ^tR> USR N 80 ^d as Methocel ' ^R »Π4Π * as Eudragit ^<R ' L 100 55 * as anhydrous' as fast flood lactose

200 mg tablets are prepared as described in section Ca).

Cb)

Ingredient mg / tablet

Doxazosin methanesulfonate 4, 876

Polyethylene oxide with molecular weight

100,000 ^p 20,000

Polyethylene oxide with molecular weight

200,000 ^c 20,000 hydroxypropyl methyl cellulose * C * methacrylic acid copolymer 60,000 60,000 Calcium phosphate * 16, 562 Laktúza 16, 562 Magnesium stearate 2, 000 Overall 200,000

equivalent of 4 mg doxazosin, based on theoretical efficacy

82.5 X ^b as Polyox ^<R> USR N 10 * = as Polyox ^tR * USR N 80 ^d as Methocel 'K4M • as Eudraglt ^<R> L 100 55 * as anhydrous' as lactose fast flo

200 mg tablets are prepared as described in Section Ca).

Example 3

Doxazosin methanesulfonate sustained release formulations with enteric coating

ca)

Ingredient mg / unit

Doxazosin methanesulfonate tablets prepared

according to example Ka) 200,000 C * methacrylic acid copolymer 6, 500 Trethylcitrate 0, 650 talc 3, 250 Sodium hydroxide 0, 090 Purified water ¹ “ C 41, 510) Overall 210, 490

As Eudraglt ^tR '100-55 ^b is lost during processing and in the final product. ¹ sa

I do not occur

All ingredients except tablets are mixed together until the methacrylic acid copolymer is dispersed. The resulting mixture is sprayed onto the tablets using conventional means to obtain a coating of the desired weight.

(B)

Ingredient mg / unit

Doxazosin methanesulfonate tablets prepared according to Example 2 (a)

C * methacrylic acid copolymer

T riety ldtr á t

talc

Sodium hydroxide

Purified water ^b

Overall

200. 000

6. 500

0. 650

3. 250

0. 090 (41,510)

210. 490 • as Eudraglt ^tR> 100-55 ^b is lost during processing and does not occur in the final product

The tablets are coated as described in (a).

(C)

Ingredient mg / unit

Doxazosin methanesulfonate tablets prepared according to Example 2 (a)

Methacrylic acid copolymer type A * Methacrylic acid copolymer type B ^b Tethyl acetate

Ammonia solution ^e

Ammonia solution water content *

talc

Purified water ^b

Overall

200. 000

3. 985

3985

3. 984

0. 058 (0.172)

3. 988 (55,555)

216 • 000 as Eudragit ^<R> L 100 ^b as Eudraglt ^<R> S 100 ^E as a solution with a density of 0.91 g / cm ³ _{(with the} 25X HLH). The aqueous component of this solution is lost during processing ^d is lost during processing and does not occur in the final product

The tablets are coated as described in section Ca). Example 4

Sustained release formulation of darifenacin hydrobromide

Ingredient mg / tablet

Darifenacin hydrobromide 'Polyethylene oxide with a molecular weight of 100 000 ¹

Polyethylene oxide with a molecular weight of 200,000 ^e

hydroxypropyl methylcellulose "

lactose *

Magnesium stearate

Overall

35, 714 by weight

20, 000 weight

20, 000, 60,000

62, 266

2, 000

200,000 * equivalent of 30 mg doxazosin based on theoretical efficacy of 84.0 X ^b as Polyox ^IR> USR N10 ^c as Polyox ^<R * WSR N80 ^d as riethocel ^<R> K4M * as anhydrous

Ii

I

200 mg tablets were prepared as described in Example 1Ca).

Example 5

Sustained-release fluconazole preparations (suitable for buccal administration)

ca)

component mg / tablet fluconazole 20,000

Polyethylene oxide with molecular weight

100000* Polyethylene oxide with molecular weight 10, 000 200,000 · 10, 000 hydroxypropyl methylcellulose ** 30,000 lactose * 29, 000 Magnesium stearate 1, 000 Overall 100000

* as Polyox ^<R> WSR N 10 * as Polyox ^<R> WSR N 80 * as Methocel ^<R> K4I * I ^d as lactose faet flo

100mg tablets were prepared as described in Example 1Ca).

C b)

component mg / tablet fluconazole Polyethylene oxide with molecular weight 10, 000 100 ooo · 7, 500 Hydroxypropylmethylcellulose ^b 22, 500 Calcium phosphate * 34, 250 Top Stearate 0, 750

Total 75.000 * as Polyox ^<R> USR N 10 ^b as Methocel * ^R 'Π4Π ⁶ as anhydrous

75 mg tablets were prepared as described in Example 1Ca).

Example 6 (comparative)

Sustained release formulation of doxazosin methanesulfonate not containing polyethylene oxide

component mg / tablet Doxazosin methanesulfonate * 3. 636 hydroxypropyl methyl cellulose * 60,000 Dibasic calcium phosphate ⁶ 67.182 Lactose ^d 67.182 Magnesium stearate 2, 000 Overall 200. 000

* equivalent of 3 mg doxazosin. based on theoretical efficiency

82.5% ^b as Methocel * ^R * K4FI ⁶ as anhydrous ^d as lactose growth flo

I

200 mg tablets were prepared as described in Example 1Ca).

Example 7

Dlsolučná analýza

The tablets prepared according to Examples 1 (a), 1 (b) and 6 are dissolved using the Apparatus 1 described in USP 22, p. 1578, method 1 with cups). The dissolution fluid was 900ml of water at 37 ° C, rotation rate of the cups is of 100 ^min-1 and the release of the drug compound is detected by UV spectrometry, at a wavelength of 246 nm. The release of drug compound (CX) versus time for each type of tablet is shown in FIG. First

The tablets prepared according to Example 2Ca) are dissolved using the Apparatus 1 described in USP 22, p. 1578, method 1 (with baskets). Solvent hydrochloric acid (100 mL); 10 liters; pH = 2) is replaced by a neutral pH medium (8.7 g); potassium chloride (47, 4 sodium hydroxide (52 ml); water until completion of the test. Frequency of liquid is 900 ml of acidic medium CIM sodium chloride (70, 2 g); water to 37 ° C, which after 2 hours potassium hydrogen phosphate g ); sodium chloride (20.3 g); IM L) to be applied to the rotation of the cups is of 200 ^min-1 and the release of the drug compound is detected by UV spectrometry, at a wavelength of 246 nm. Time-dependent release of drug compound (X) is shown in Figure 2.

Claims (24)

PATENT CLAIMS Controlled release pharmaceutical composition for oral administration, characterized in that it is essentially composed of an active drug compound: low molecular weight polyethylene oxide; the hydroxypropyl; tableting excipients; and optionally at least one enteric polymer. 2. A pharmaceutical composition according to claim 1, wherein the active drug compound is weakly basic. Pharmaceutical composition according to claim 1 or 2, characterized in that the active drug compound is doxazosin or a pharmaceutically acceptable salt thereof. Pharmaceutical composition according to claim 1, characterized in that. that the active drug compound exhibits high solubility in aqueous media. The pharmaceutical composition of claim 1, wherein the active drug compound exhibits low solubility in aqueous media. Pharmaceutical composition according to any one of the preceding claims, characterized in that the hydroxypropylmethylcellulose has a number average molecular weight of Θ0,000 to 2,50,000. Pharmaceutical composition according to any one of the preceding claims, characterized in that the hydroxypropylmethylcellulose has a degree of methyl substitution in the range of 19 to 30%. Pharmaceutical composition according to any one of the preceding claims, characterized in that the hydroxypropylmethylcellulose has a degree of hydroxyl substitution in the range of 4 to 12%. Pharmaceutical composition according to any one of the preceding claims, characterized in that the polyethylene oxide has a number average molecular weight in the range of 200,000 to 500,000. 10. A pharmaceutical composition according to claim 9 wherein the polyethylene oxide has a number average molecular weight in the range of 100,000 to 300,000. Pharmaceutical composition according to any one of the preceding claims, characterized in that the enteric polymer is mixed with the other ingredients of the composition. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises a coating comprising an enteric polymer. A pharmaceutical composition according to claim 11 or 12, wherein the enteric polymer is a methacrylic acid copolymer. A pharmaceutical composition according to any one of the preceding claims. characterized in that it contains up to 50% by weight of the effective HeCl2 compound. Pharmaceutical composition according to any one of the preceding claims, characterized in that it contains 50 to 30% by weight of low molecular weight polyethylene oxide. Pharmaceutical composition according to one of the preceding claims, characterized in that it contains 10 to 60% by weight of hydroxypropylmethylcellulose. Pharmaceutical composition according to any one of the preceding claims, characterized in that: The composition of claim 1, wherein said composition comprises from 10 to 40% by weight of an enteric polymer mixed with the other ingredients of the composition. Pharmaceutical composition according to any one of the preceding claims, characterized in that the weight ratio of low molecular weight polyethylene oxide to hydroxypropylmethylcellulose is in the range of from 2 to 5. ^_ 19. A composition according to any one of claims 11 to 19, vyznafiujúcl in that the weight ratio of the amount of polyethylene oxide-ceiling low molecular weight and the hydroxypropyl the amount of admixed enteric polymer is in the range of 1 <2-6 '1. 20. The pharmaceutical composition of claim 19, wherein the weight ratio of the amount of low molecular weight polyethylene oxide e and hydroxypropylmethylcellulose to the amount of blended enteric polymer is in the range of 1 * 2 to 2 * 1. Pharmaceutical composition according to any one of claims 12 to 20, characterized in that the enteric coating comprises 2 to 15% by weight of the composition. The pharmaceutical composition of claim 21, wherein the enteric coating comprises 5 to 10% by weight of the composition. I I Use of low molecular weight polyethylene oxide in controlled release oral pharmaceutical compositions comprising a hydroxypropylmethylcellulose matrix to enhance erosion of the matrix after a predetermined period of time from administration to the patient. The use of claim 23, wherein the predetermined time is 6 hours. 25. A process for the production of a pharmaceutical composition according to claim 1, wherein the active compound is mixed; low molecular weight polyethylene oxide; hydroxypropyl methylcellulose; tableting exdplents; and optionally at least one enteric polymer; and the resulting mixture is then compressed into tablets.