CA1297017C - Controlled release pharmaceutical composition - Google Patents

Abstract

ABSTRACT

A solid, controlled release, pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water soluble polydextrose.

The controlled release matrix may also contain at least one of a digestible C8-C50 substituted or unsubstituted hydrocarbon, especially a C12-C36 fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol.
Optionally, the matrix may contain a cellulose ether, especially a hydroxyalkylcellulose or a carboxyalkylcellulose.

Description

Ref: P/0195 ~ 7~, ~7 CB3AAB

CONTROL~ED RE~EASE_PHARMACEUTICAL COMPOSITION

The present invention relates to a solid controlled release pharmaceutical composition.

A "controlled release pharmaceutical composition" is one that achieves slow release of a drug over an extended period of time and extends the duration of drug action over that achieved by conventional delivery. Preferably, such a composition maintains drug level in the blood or target tissue within the therapeutic range for 8 hours or more.

A controlled (sustained) release pharmaceutical c~mposition containing an active ingredient has many advantages over a normal release form of the same ingredient. These include a reduction of the frequency of administration, a decrease in side effects and the maintenance of effective concentrations of the active material in the blood.

Accordingly, a large number of controlled release forms have been prepared in the past few years. For example, the composition may contain a large amount of an excipient that disintegrates slowly in the stomach or intestines.
Alternatively, granules or tablets containing the active ingredient may be covered with a gastro-resistant coating or with a semipermeable membrane. A further device is to mix the active ingredient with a hydrophilic polymer.

Of these controlled release forms, the use of hydrophilic polymers (in matrices for active ingredients) has been particularly successful. Amongst the most widely used of these hydrophilic polymers are hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

,3 : : ~

,.' , 0~7 It is an object of the present invention to provide a controlled release pharmaceutical cornposition containing a hydrophilic polymer that, in controlled release formulations, exercises better control over the release of the active ingredient than a hydroxyalkylcellulose.

Other objects and advantages of the present invention will become apparent from the following detailed description thereof .

According to the present invention, therefore, there is provided a solid, controlled release, pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water-soluble polydextrose.

In the present specification, a "water soluble polydextrose"
is a polydextrose that dissolves to a level of at least 1%
(w/w) in water at 25C.

Although the polydextrose employed in the present composition may have an average molecular weight of between about 360 and 106j preferably the polydextrose has a number average molecular weight ~etween 1000 and 12000. Polydextrose is a non-nutritive polysaccharide, prepared by the condensation polymerisation of saccharides in the presence of polycarboxylic acid catalysts, under reduced pressure Polydextrose is ~escribed in US Patents No. 3766105 and 3786794 and is available from Pfizer Inc., New York. Commercially available polydextrose polymer is generally a low molecular weight, water-soluble, randomly bonded polymer of glucose containing minor amo~mts of sorbitol end groups and citric acid residues attached to the polymer by ., .
,: .

3 ~X~970:L7 mono- and di-ester bonds. ~he number average molecular ~eight of this commercially available material is 1500, ranging from about 360 to about 20,000.

The amount of polydextrose present in the composition of this invention will be determined by a number of factors, including the active ingredient to be administered and the rate of drug release required. Preferably, however, the composition will contain between 1% and 80% (w/w), especially between 1% and 50% (w/w) of polydextrose, most especially between 2% and 40%
(w/w) of polydextrose.

In addition to the polydextrose, the present composition may also include further ingredients which can contribute to the control of the active ingredient's release and are compatible with polydextrose.

Suitable materials are, (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers and protein derived materials. Of these polymers, the cellulose ethers, especially hydroxyalkyl celluloses and carboxyalkylcelluloses, most especially hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-propylmethylcellulose and sodium carboxymethylcellulose, are preferred.
(b) Digestible, long chain (Cg C50, especially Cg-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral oils and waxes.
Preferably the hydrocarbons have a melting point between 25 and 90C. Of these long chain hydrocarbon materials, fatty alcohols, most especially Cl4-C22 fatty alcohols, such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or . . . .
' - ~

1.7 myristyl alcohol are preFerred.

(c) Polyalkylene glycols, especially polyethylene glycol.

At least one of the materials within categories (b~ and (c) is particularly preferred.

When the polydextrose is combined with at least one of a digestible, C8-C50 substituted or unsubstituted hydrocarbon and a polyalkylene glycol, the matrix itself is novel. Thus, in another aspect of the present invention, there is provided a preparation for use in the production of a solid, controlled release pharmaceutical composition comprising a matrix of polydextrose and at least one of a digestible Cg-Cso substituted or unsubstituted hydrocarbon and a polyalkylene glycol. Optionally, the matrix may also contain at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose.

In a particularly preferred embodiment of the present composition, the matrix comprises polydextrose; at least one of a C12-C36 fatty alcohol and a polyalkylene glycol and, optionally, at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose. In such an embodiment the ratio of polydextrose/cellulose to fatty alcohol/glycol is preferably between 6 to 1 and 1 to 6, especially between 4 to 1 and 1 to 4. Preferably a C14-C22 fatty alcohol is employed.

This matrix is also a novel composition and, therefore, according to a further aspect of the present invention, there is provided a preparation for use in the production of a solid, controlled release, pharmaceutical composition comprising a matrix of polydextrose, at least one of a C12-C36 fatty alcohol and a polyalkylene glycol and, optionally, at least one of a hydroxyalkylcellulose and a .. . . . . . .

, : , , . .

, .
' . . .~
.
.

~2~7q~
s carboxyalkylcellulose. Preferably the macrix comprises a C14 C22 fatty alcohol.

In addition to the above materials, the oresent controlled release composition may also contain excipients such as binders, disintegrating agents, colours, flavours, preservatives7 stabilisers, glidants and lubricants, the use of which will be known to those skilled in the pharmaceutical art.

Although the present controlled release composition may be in any solid dosage form, for example, a suppository or a pessary, it is preferably adapted for oral administration. In the present specification "oral administration" incorporates buccal and sublingual administration. Thus, the preferred oral dosage forms include tablets, buccal tablets, sublingual tablets, pills, lozenges, capsules containing, for example, granules or pellets, and dragees.

Any active ingredient that may be administered by the oral, buccal, sublingual, rectal or vaginal routes may be employed in the controlled release composition of this invention.
Those medicaments haYing a biological half-life below about 8 hours, however, are particularly suitable for incorporation in the present composition.

Examples of active ingredients that may advantageously be incorporated in the present composition are, 1) Anti-allergic drugs~ such as cyclizine, dimethindene maleate and trlprolidlne hydrochloride, 2) Anti-diabetic drugs, such as chlorpropamide, ylibenclamide~ metformln and tolbutamide, .
.
.

.

' ~L~97~

3) Hormones, ~) Antiarrhythmic agents, such as disopyramide, procainamide, propranolol and quinidine, 5) Anti-inflammatory agents, such as aspirin, diclofenac sodium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen and phenylbutazone, 6) Antiemetic arugs, such as metoclopramide, 7) Diuretics, such as amiloride, bendrofluazide, bumetanide, cyclopenthiazide, ethacrynic acid, frusemide, hydrochlorothiazide, triampterene, chlorthalidone and spironolactone, 8) Anti-anginal agents, such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, verapamil and diltiazem, 9) Vasoailators, such as nifedipine, naftidrofuryl oxalate, and nicardipine, 10) Antihypertensive agents, such as clonidine, indoramin, guanethidine, methyldopa, oxprenolol, captopril, hydralazine~and propranolol, 11) Bronchodilators, such dS salbutamol, isoprenaline and terbutaline, 12) CNS stimulants, such as caffeine and amphetamine, 13) Anti-histamines, such as clemastine fumarate, mepyramine, chlorpheniramine, brompheniramine, :

7 ~2~7~ ~7 diphenhydramine.

14) Analgesic agents, such as morphine, codeine, phenazocine, dihydrocodeine, hydromorphone, meptazinol, phenacetin, pethidine, paracetamol, oxycodone~ diamorphine, nalbuphine, buprenorphine, and mefenamic acid, 15) Vitamins, such as Vitamin B1, Vitamin B2, Vitamin B6, Vitamin C and Vitamin E, 16) Antidepressants, such as lofepramine, amitriptyline, doxepin, maprotiline, imipramine, desipramine and mianserin, 17) Tranquilisers, such as chlordiazepoxide and diazepam, 18) Hematinic agents, such as ferrous fumarate, 19) Respiratory stimulants, such as nikethamide, ZO) Antibacterial agents, such as polymyxin, streptomycin, sulphonamides, penicillins, erythromycin, cephalosporins, nalidixic acid, tetracyclines, hexamine salts, gentamicin ; and nitrofurantoin, :: :
21) Hypnotic agents such as barbiturates, dichloral ~: phenazone, nitrazepam and temazepam, : :::
~ ~ 22) Antiviral agents, such as idoxuridine, ~: :
~: 23) ~asoconstrictors, such as angiotensin amide, dihydroergotamine, and ergotamine, 24) Topical anaesthetics, such as benzocalne, : ~

:

`'' :: ~ , 25) Anticholinergic agents, such as scopolamine, atropine and propantheline, 26) Adrenergic drugs, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride and pseudoephedrine, 27) Anthelmintic agents, such as diethylcarbamazine, 28) Corticosteroids, such as dexamethasone, prednisone, prednisolone and triamcinolone acetonide, 29) Inorganic drugs, such as lithium carbonate, potassium chloride and lithium sulphate, 30) Antacids, such as aluminium trisilicate and aluminium hydroxide, 31) Antiulcer agents, such as cimetidine and ranitidine, 32) Cofactors, such as nicotinic acid, 33) Antipsychotic agents, such as thiorida~ine, trifluoperazine, fluphenazine and haloperidol, 34) laxatlves, such as bisacodyl and magnesium hydroxide, 35) Antiperistaltic agents, such as diphenoxylate9 36) Anticoagulant agents, such as warfarin, 37) Haemostatic agents, such as epsilon-aminocaproic acid, :
: 38) Antinauseant agents, such as metoclopramide, pyridoxine and prochlorperazine, :
:
-. . .
, :.. - . . , .. :- . .

.. . ..

.

g 39) Anticonvulsant agents, such as sodium valproate and phenytoin sodium, 40) Neuromuscular drugs, such as dantrolene sodium, 41) Hypoglycaemic agents, such as chlorpropramide1 glucagon and tolbutamide, 42) Thyroid drugs, such as thyroxine, triiodothyronine and propylthiouracil, 43) Uterine relaxant, such as ritodrine, 44) Appetite suppressants, such as phentermine, diethylpropion HCl and fenfluramine HCl, 45) Erythropoietic substances,such as folic acid, calcium gluconate, and ferrous sulphate, 46) ~xpectorants, such as carbocisteine and, guiaphenesin, 47~ Cough suppressants, such as noscapine, dextromethorphan and oxycodone, 48) Antluricaemic drugs, such as allopurinol, probenecid and sulphinpyrazone, .

.

When the present controlled release matrix contains polydextrose, but no digestible, long chain substituted or unsubstituted hydrocarbon or polyalkylene glycol, the active ingredient is preferably a water-inso7uble drug. In the present specification, a water insoluble drug is a drug that dissolves in water (pH 5) at 20C to a concentration of less than 1.0mgml~1, preferably less than 0.5mgml~1.

According to ano~her feature of the present invention, the solid, controlled release, pharmaceutical composition is prepared by mixing an active ingredient with a water soluble polydextrose, optionally in the presence of one or more of thP
following excipiencs, a hydrophilic or hydrophobic polymer (other than polydextrose), a digestible long chain, substituted or unsubstituted hydrocarbon, a polyalkylene glycol, a bin~er, a disintegrating agent, a granulating aid, a colour, a flavour, a preservative, a stabiliser, a lubricant and a glidant.

Preferably, the active ingredient is mixed with polydextrose and, at least, a C12-C36 fatty alcohol, especially a C14-C22 fatty alcohol such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol, and/or a polyalkylene glycol, especially polyethylene glycol.

In a particularly ~referred embodiment of this feature of the invention a solid, controlled release, pharmaceutical composition, in unit dosage form and for oral administration (as hereinbefore defined), is prepared by granulating an active ingredient with a water soluble polydextrose and, optionally, mixing with one or more of the following excipients, a hydrophilic or hydrophobic polymer (other than polydextrose), a digestible, long chain, substituted or unsubstituted hydrocarbon, a polyalkylene glycol, a binder, a disintegrating : ' ; ,: ~ . ' ' agent, a colour, a flavour, a preservative, a stabiliser, a lubricant, a glidant, to form granules and compressing the granules to give an oral, solid, unit dosage form containing a predetermined, therapeutically active, quantity of the active ingredient.

Depending on the particular case, the method of preparation of the granules may involve for example wet granulation or direct compression.

Preferably, the active ingredient is granulated with polydextrose and the granules formed are mixed with a C12-C36 fatty alcohol, especially a C14 C22 fatty alcohol such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol, and/or a polyalkylene glycol, especially polyethylene glycol.

Once the oral, solid unit dosage form has been prepared it may, if desired, be coated for example, with a gastro-resistant coating.

In a further, particularly preferred embodiment of this feature of the invention a solid, controlled release, pharmaceutical composition in the form of a capsule is prepared by pelletising, spheronising or granulating an active ingredient with a water-soluble poly~extrose and, optionally, one or more of the optional ingredients employed in the preparation of the oral, unit dosage form above, to form pellets, spheroids or granules and encapsulating the pellets, spheroids or granules to give a capsule containing a predetermined, therapeu~ically active9 quantity of the active ingredient ,. ~

j . .

~2~ 7 Prior to filling the capsule with the pellets, the spheroids or the granules, the pellets/spheroids/granules may be coated, for example with a gastro-resistant coating.

According to another feature of the present invention, there is provided a process for the preparation of a matrix for admixture with an active ingredient to form a controlled release pharmaceutical composition comprising mixing a water soluble polydextrose with at least one of a digestible, Cg~Cso substituted or unsubstituted hydrocarbon and a polyalkylene glycol. Preferably the polydextrose is mixed with at least one of a C12-C36 fatty alcohol (especially C1~-C22) and a polyalkylene glycol, especially polyethylene glycol. The mixing stage is preferably a granulation step.

Once the matrix has been granulated it can then be mixed with a predetermined amount of the active ingredient an~, optionally compressed, to give a controlled release pharmaceutical composition according to this invention.

Predetermined release patterns of unusually reliable and constant characteristics can be secured using the present composition. This is often very important medically, especially when treating patients having coronary diseases 9 such as angina pectoris, or related problems, such as circulatory disorders or abnormal blood pressure, or when treating psychotropic disorders, such as manic depression or schizophrenia or when treating bronchial disorders or moderate to severe pain. The present composition may also be extremely useful in the treatment of ulcerated tissues or mucous lesions and other conditions which arise from local hyperacidity or metabolic dysfunction in the physiological system. The present composition is therefore ex~remely versatile and adaptable giving a wide range of application and end use.

-,- , :

.: ' ~

13 ~ ~ g 7 ~

The present solid, controlled release, pharmaceutical composition, together with methods for its preparation will now be described by way of example only, with particular reference to the Figures in which, Figure 1 illustrates the control exercised over theophylline release by polydextrose, as measured by in vitro dissolution, Figure 2 compares the release rates of two theophylline controlled release formulations, one containing hydroxyethylcellulose, the other polydextrose, Figure 3 compares the release rates o~ two pyridoxine hydrochloride controlled release formulations, one containing hydroxyethylcellulose, the other polydextrose, and Figure 4 compares the releasP rates of two metoclopramide hydrochloride controlled release formulations, one - containing hydroxyethylcellulose, the other po 1 ydextrose .

Example 1 (Comparative) Anhydrous theophylline (40gm) was dry mixed with anhydrous lactose tl5gm), microcrystalline cellulose (5gm) and crosslinked carboxymethyl cellulose (2gm; Croscarmellose). The mixture was granulated with water until a wet granular mass was obtained. The wet material was then sieved through a 16 mesh screen. The granules were then dried in a Fluid Bed Dryer (FBD) at 60C. Finally, magnesium stearate (0.5gm) was added to and mixed with the granules, which were then compressed to give 100 tablets each containing, ` ~' . :

.
, ~

9701~
1~

mg/tablet Theophylline anhydrous ~00 Lactose anhydrous 150 Microcrystalline cellulose 50 Crosslinked carboxymethylcellulose 20 Magnesium stearate 5 Example 2 Anhydrous theophylline (40gm) was wet granulated with polydextrose (2.5gm) and the granules were sieved through a 16 mesh screen. The granules were then dried in an F8D at 60C.
Talc (1.Ogm) and magnesium stearate (1.Ogm) were then added and mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/tablet Theophylline anhydrous 400 Polydextrose 25 Talc 10 Magnesium stearate 10 A comparison of the release rates of theophylline from tablets prepared as described in Examples 1 and 2 is shown in Figure 1. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5).

Example 3 (Comparative) Anhydrous theophylline (409~) was wet granulated with hydroxyethylcellulose ~2.5gm; Natrosol 250HX, Trade Mark) and the granules were sieved through a 16 mesh screen. The granules were then dried in a FBD at 60C.

To the warmed theophylline containing granules was added a molten mixture of polyethylene glycol (PEG) 6000 (5.0gm~ and, , ' . .......... . : ' -.

~f~9'7~

cetostearyl alcohol (4.0gm). This mixture was allowed to air cool and then passed through a 16 mesh screen.

Talc (1.Ogm) and magnesium stearate (1.Ogm) were then mixed with the granules. The granules were compressed to give 100 tablets each containing, mg/tablet Theophylline anhydrous 400 Hydroxyethylcellulose 25 Cetostearyl alcohol40 Talc 10 Magnesium stearate 10 Example 4 The procedure of Example 3 was followed except that polydextrose replaced the hydroxyethylcellulose. Thi, gave 100 tablets, each containing mg/tablet Theophylline anhydrous 400 Polydextrose 25 Cetostearyl alcohol40 Talc 10 Magnesium stearate 10 A comparison of the release ra~es of theophylline from tablets prepared as described in Examples 3 and 4 is shown in Figure 2. The dissolution rates were measured by the USP Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH 6.5).

~ ~ ' ' ' ' ' ' : . .. , ~ ''~' :

' 16 ~ 2 Example 5 (Comparative) Pyridoxine hydrochloride (lOgm) and hydrogenated castor oil (l.Sgm) ~ere granulated with hydroxyethylcellulose (2.0gm, Natrosol 250HX) and the granules were sieved through a 16 mesh screen and dried in a F8D at 60C.

To the pyridoxine HCl containing granules, molten cetostearyl alcohol (3.5gm) was added. This mixture was allowed to air cool an~ then passed through a 16 mesh screen.

Talc (0.3gm) and magnesium stearate (O.lgm) were mixed with the granules. This mixture was compressed to give 100 tablets each containing, mg/tablet Pyridoxine HCl 100 Hydroxyethylcellulose 20 Hydrogenated castor oil 15 Cetostearyl alcohol 35 Talc 3 Magnesium stearate Example 6 The procedure of Example 5 was followed except that polydextrose replaced the hydroxyethylcellulose. This gave 100 tablets each containing, mg/tablet Pyridoxine HCl 100 Polydextrose 20 Hydrogenated castor oil 15 Cetostearyl alcohol 35 Talc Magnesium stearate :., , . ' : . : . .

, : ' ' ' ~29~1.7 A comparison of the release rates of pyridoxine HCl from tablets prepared as described in Examples 5 and 6 is shown in Figure 3. The dissolution rates were measured by the USP
Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH
6.5).

Example 7 (Comparative) Metoclopramide HCl (3gm) was wet granulated with anhydrous lactose (17gm) and hydroxyethylcellulose (2gm; Natrosol 250HX) and the granules were sieved through a 16 mesh screen. The granules were then dried in an FBD at 60C.

To the warmed metoclopramide containing granules was added molten cetostearyl alcohol (7gm). The mixture was allowed to air cool and then passed through a 16 mesh screen~

Talc (0.6gm) and magnesium stearate (0.4gm) were mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/tablet Metoclopramide HCl 30 Anhydrous lactose 170 Hydroxyethylcellulose 20 Cetostearyl alcohol70 Talc 6 Magnesium stearate 4 Example 8 Anhydrous lactose (17grn) and polydextrose (2gm) were dry mixed. Molten cetostearyl alcohol (7gm) was added to the dry mixed powders. The mixture was allowed to cool and passed ~hrrugh a 16 mesh screen.

,, .
- .
:
. .

. . .::

~7~

Metoclopramide HCl (3gm), talc (6gm) and magnesium stearate (4gm) were then mixed with the polydextrose/wax granules and then compressed to give 100 tableCs each containing, mg/tablet Metoclopramide HCl 30 Anhydrous lactose 170 Polydextrose 20 Cetostearyl alcohol 70 Talc 6 Magnesium stearate 4 A comparison of the release rates of metoclopramide HCl from tablets prepared as described in Examples 7 and 8 is shown in Figure 4. The dissolution rates were measured by the USP
Paddle Method at 100 rpm in 900 ml of aqueous buffer (pH
6.5).

Example 9 Anhydrous theophylline (40gm) was wet granulated with polydextrose (21.8gm) and the granules were sieved through a 16 mesh screen. The granules were dried in a FBD at 60C.

To the warmed theophylline containing granules was added a molten mixture of polyethylene glycol 6000 (2.9gm), polyethylene glycol 1000 (1.45gm) and cetostearyl alcohol (2.9gm). This mixture was allowed to air cool and then passed through a 16 mesh screen.

Talc (1.Ogm) ana magnesium stearate (0.45gm) were then mixed with the granules. The granules were compressed to give 100 tablets each containing, .

- . . - .
- . :
.
': :
:~ , ~2~73~
l9 mg/Tablet Theophylline anhydrous 400 Polydextrose 218 PEG 1000 14.5 Cetostearyl alcohol 29 Talc 10 Magnesium stearate 4~5 The in-vitro dissolution rate of these tablets were measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are shown in Table 1.

-In vitro D ssolution of Theophylline Tablets Time (Hours) % (by wt) Released -- --.T--. _ .. . ~ .

2 21.7 4 33.7 6 42.3 8 49.0 12 58.3 14 62.0 16 65.0 18 67.8 Example 10 Naproxen (50gm), dicalcium phosphate (16.4gm), lactose (2.5gm), polydextrose (2.0gm) and hydroxypropylmethylcellulose (2.0gm) were wet granulated and the granules were sieved through a 16 mesh screen. The granules were then dried in a - .:
. ,~ : " - , .
- , .

.

~25~7~ 1~7 FBD at 50C. Talc (1 35grn) and magnesium steara~e (0.75gm) were then added and mixed with the granules. The granules were then compressed to give 100 tablets each containing ~'~
Naproxen 500 Dicalcium phosphate, anhydrous164 Lactose monohydrate 25 Polydextrose 20 Hydroxypropylmethylcellulose 20 Talc 13.5 Magnesium stearate 7.5 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rprn in 900ml of aqueous buffer (pH
7.2). Results are shown in Table 2.

In Vitro Dissolution of Naproxen Tablets Time (Hours) % (by wt) Released . . _ .

1 22.3 2 49.9 3 74.4 4 91.1 95.9 Example 11 Naproxen (50gm), lactose (11.25gm), polydextrose (0.75gm) and povidone (2.0gm) were wet granulated and the granules were sieved through a 16 mesh screen. The granules were dried in a I:BD at 60'C Talc (1.2gm) and magnesium steara~e (0 6gm) were .

.
' ~g~Ql~

mixed with the granules. The granules were compressed to give 100 tablet cores each containing, _g/tablet Naproxen 500 Lactose monohydrate 112.5 Polydextrose 7-5 Povidone 20 Talc 12 Magnesium stearate 6 The ta~let cores were then coated with an aqueous formulation (lOOml) containing polyvinylacetate phthalate (l5gm) and 0.88 ammonia solution (0.18ml) until the cores were coated with about 20mg (dry weight) of coat.

The in-vitro dissolution rate of these tablets was measured by placing the tablets in 0.1N hydrochloric acid for 2 hours and thereafter continuing the USP Paddle Method at 130rpm in 900ml of aqueous buffer pH 7.2. Results are shown in Table 3.

In Yitro Dissolution of Naproxen Tablets Time (Hours) Medium% (by wt? _eleased 1 0.1N Hydrochloric Acid O
2 0.1N Hydrochloric Acid O
3 pH 7.2 buffer 12.5 4 pH 7.2 buffer 28.3 pH 7.2~ buffer 43.4 6 pH 7.2 buffer 60.3 7 pH 7.2 buffer 71.9 :

: .

, . .

~70i:17 8 pH 7.2 buffer 78.6 pH 7.2 buffer 85.3 12 pH 7.2 buffer 88.1 14 pH 7.2 buffer 92.1 Example 12 Polydextrose (28gm) was mixed with a mixture of molten cetostearyl alcohol (6grn) and polyethylene glycol 4000 (6gm).
The granules were allowed to cool and sieved through a 20 mesh screen.

Theophylline (40gm) was granulated with a solution of povidone (1.2gm) in water. The granules were sieved through a 12 rnesh screen and dried in a fluid bed drier. The granules were then sieved through a 20 mesh screen.

The theophylline granules and the polydextrose/wax granules were dry mixed with purlfied talc (0.6gm). Prior to cornpression, magnesium stearate (0.6gm) and purified talc (0.6gm) were mixed with the granules. This mixture was then compressed to give lO0 tablets each containing, mg/Tablet Theophylline 400 Povidone 12 Polydextrose 280 Cetostearyl Alcohol 60 Polyethylene Glycol 4000 60 Purified Talc 12 Magnesium Stearate 6 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at lOOrpm in 900ml of aqueous buffer : ~ .
:
::
.: , ~: , .

~297t:1~7 (pH 6.5). Results are shown in TABLE 4.

In Vitro Dissolution of Theophylline Tablets _ _ Time_ Hours? % (by wt) Released 1 10.3 2 15.3 4 22.8 8 33.9 12 42.3 1~ 48.4 24 61.4 Example 13 The procedure of Example 12 was followed except that the amounts used were chosen such that each tablet contained, m~/tablet Theophylline 400 Povidone 12 Polyaextrose 140 Cetostearyl Alcohol 30 Polyethylene Glycol 4000 30 :~ : Purified Talc 9 Magnesium Stearate 4.5 The in-vitro dissolution rate of these tablets was measured as described in Example 12. Results are given in TABLE 5.

::

~: :
' :
,:

24 ~ 2 ~ 7 ~ l 7 TAB~E 5 In Vitro Diss_lution of Theophylline Tablets Time (Hours) X (by wt) Released 10 .9 2 16.4 4 24.5 8 35.6 12 45.5 16 54.5 .
24 72.2 Example 14 The procedure of Example 12 was -Followed except that the amounts used were chosen such that each tablet contained, ~ '.
Theophylline 400 Povidone 12 Polydextrose 93.3 Cetostearyl Alcohol 20 Polyethylene Glycol 4000 20 Purified Talc 8 Magnesium Stearate 4 The in-vitro dissolutin rate of these tablets was measured as described in Example 12.~ Results are given in TABLE 6.

: :

.

, , .

~ able~s _me (Hours) ~ (by wt) Released 1 12.4 2 19.2 4 29.5 8 44.~
12 56.5 16 68.6 24 91.9 Example 15 The procedure of Example 12 was followed except that the amounts used were chosen such that each tablet containe~, mg/Tablet Theophylline 400 Povidone 12 Polydextrose 70 Cetostearyl Alcohol 15 Polyethylene Glycol 4000 15 Purified Talc 7.8 Magnesium Stearate 3.7 The in-vitro dissolution rate of these tablets was measured as described in Example 12. Results are given in TABLE 7.

;: ~ :

, , ~ .

26 ~ ~ ~3 In Vitro Dissolution of TheoDhylline Tablets .., Time (Hours) % ~by_wt) Released 1 12.7 2 19.6 4 30.9 8 ~.6 12 66.
16 80.~
24 9~ 5 Example 16 Theophylline (40gm) and polydextrose (21.8gm) were mixed and granulated with water. The granules were dried in a fluid bed drier. The dried granules were sieved through a 16 mesh screen. The dried granules were mixed with a molten (70C) mixture of PEG 6000 (2.9gm) and octyl alcohol (2.9gm). The "waxed" granules were then cooled, before blending with talc (1.0gm) and magnesium s~earate (0~4gm). Compression of the granules gave 100 tablets each containing, m~/Tablet Theophylline 400 Polydextrose 218 Polyethylene Glycol 6000 29 Octyl Alcohol 29 Purified Talc 10 Magnesium Stearate 4 Examples 17-22 The procedure of Examp~e 16 was followed except that the octyl `
:
.. ~

- . : .

, ~
:: . . . . .

7~}~7 alcohol was replaced by, respectively, decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol~ stearyl alcohol and cetostearyl alcohol.

Example 23 Polydextrose (12.6gm) was mixed with molten cetostearyl alcohol (5.4gm). The granules were allowed tO cool and sieved through a 20 mesh screen.

Metoclopramide HCl (3.0gm) was dry mixed with the polydextrose/alcohol granules and purified talc (0.21gm).
Prior to compression, magnesium stearate (0.21gm) and purified talc (0.21gm) were mixed with the granules. This mixture was then compressed to give 100 tablets each containing, mg/Tablet Metoclopramide HCl 30 Polydextrose 126 Cetostearyl Alcohol 54 Purified Talc 4.2 Magnesium Stearate 2.1 Example 24 The procedure of Example 23 was followed except that the amounts used were chosen such thal each tablet contained, mg/Tab ? et Metoclopramide HCl 30 Polydextrose 210 Cetostearyl Alcohol 90 Purified Talc 6.6 Magnesium Stearate 3-3 :, . .. ...
, .
,. , . .

~8 ~ 7~17 Example 25 The procedure of Example 23 was followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Metoclopramide HCl 30 Polydextrose 420 Cetostearyl Alcohol 180 Purified Talc lZ.6 Magnesium Stearate 6.3 Example 26 Salbutamol sulphate (0.964gm), equivalent to 0.8gm base salbutamol was wet granulated with anhydrous lactose (20.8gm), polydextrose (1.25gm) and povidone (0.3gm) and the granules were sieved through a 16 mesh screen. The granules were then dried in a FBD at 60C.

To the warmed salbutamol containing granules was added molten cetostearyl alcohol (5.5gm). The mixture was allowed to air cool and then passed through a 16 mesh screen.

Talc (0.8gm) and magnesium stearate (0.4gm) were mixed with the granules. The granules were then compressed to give 100 tablets each containing, mg/Tablet Salbutamol Sulphate 9.64 Lactose, anhydrous 208 Polydextrose 12.5 Povidone (K30) 3 Cetostearyl Alcohcl 55 Tal G 8 Magnesium Stearate 4 .

.

. ' : .

~2~7~17 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Results are given in TABLE 8.

In Vitro Dissolueion of Salbutamol Tablets ___ Time (Hours) % (by wt) Released _ 1 49.5 2 62.4 3 - 73.2 4 79.1 85.5 6 91.0 Example 27 The procedure of Example 26 was followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Salbutamol Sulphate 9.64 Lactose, anhydrous 190.36 Polydextrose 30 Povidone (K30) 3 Cetostearyl Alcohol 55 Talc ~ 8 Magnesium Stearate 4 The in-vitro dissolution rate of the tablets was measured as described in Exa-ple 26. Results are given in T~ELE 9.

' .. - . . : ,, .... ' .. ,:

~7~7 In Yltro Dissolut-on of Salbutamol Tab!ets Time (Hours)X ~by wt) Released 1 43.8 2 61.1 3 71.4 4 77.9 80.g 6 82.3 Example 28 The procedure of Example 26 was Followed except that the amounts used were chosen such that each tablet contained, mg/Tablet Salbutamol Sulphate 9.64 Lactose, anhydrous160.36 Polydextrose 60 Povidone 3 Cetostearyl Alcohol 55 Talc 8 Magnesium Stearate 4 The in-vitro dissolution rate of these tablets was measured by ~he USP Paddle Method at 100rpm in 900ml of aqueous buffer (pH 6.5). Resul~s are given in TABLE 10.

:

~ .
.
, ~L2S~

In Vitro Dissolution of Salbutamol Tablets .. . _ _ . _ . .. .. _ Time (Hours)~, (by wt) Released .

1 41.0 2 57.8 68.0 4 74.6 81.0 6 83.1 Example 29 Quinidine polygalacturonate (41.25gm), lactose (4.5gm), hydroxypropylmethyl cellulose (1.25gm) and polydextrose (4.5gm) were granulated with water. The granules were sieved through a 16 mesh screen and dried in a fluid bed drier. The granules were mixed with molten cetostearyl alcohol (9.Ogm) and allowed to cool. The granules were sieved through a 16 mesh screen and blended with purified talc (1.Ogm). The granules were compressed to give 100 tablets each containing, mg/Tablet Quinidine Polygalacturonate412.5 ~actose 45 Hydroxypropylmethyl cellulose 12.5 Polydextrose 45 Cetostearyl Alcohol 90 Purified Talc 10 .
The in-vitro dissolu~ion rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml of buffer (pH 6.5).
Results are given ln TABLE 11.

. . .

. ,, .~ , . 1 , . . .

~9~ti7 In Vitro Dissolution of Quinidine Tablets Time (Hours? % (by wt) Released 1 15.2 2 26.0 4 ~1.5 8 60.1 12 72.5 89.g Example 30 Nifedipine (2.0gm), lactose (8.0gm) and polydextrose (2.0gm) were mixed and granulated with aqueous povidone solution (0.7gm Povidone K30). The granules were dried in a fluid bed drier. The dried granules were sieved through a 20 mesh screen before blending with purified talc (0.4gm) and magnesium stearate (0.2gm). The granules were compressed to give 100 tablets each containing, my/Tablet NiFedipine 20 Eactose, anhydrous 80 Polydextrose 20 Povidone K30 7 Purified Talc 4 Magnesium Stearate 2 The in-vitro dissolution rate of these tablets was measured by the USP Paddle Method at 100rpm in 900ml aqueous isopropyl alcohol (4:1 (v/v); water i-PrOH). Results are given in TABEE 12.
s ' .
; , , , - ~ .
.

~2 ~3 n Vitro Diss lution of Nifedipine Tablets Time (Hours~ X tby wt) Released 1 8.9 2 18.9 3 54.0 4 87.7 96.1 6 99.2 CLINICAL STUDIES
. _ A pharmacokinetic study in 3 healthy volunteers was performed on tablets prepared as described in Ex~ample 9. Samples were analysed by enzyme immunoassay. Meah plasma theophylline concentrations are given in TABLE 13.

Time (Hours) Mean Plasma Theophylline Concentration tug/ml) O .
: 1 2 1.6 3 2.1 4 2.7 3 r3 : 6 3.3 7 ~ 3~0 1, , , . '. ' : ~ ' ~l%~7~17 8 3.0 2.5 12 2.1 24 ' 1.4 It can therefore be seen that the composition of Example 9 exhibits excellent control over the release of theophylline in vivo.

. ~ :
-.

Claims (32)

1. A process for the preparation of a solid controlled release, pharmaceutical composition comprising mixing an active ingredient with a water soluble polydextrose to for a controlled release matrix incorporating the active ingredient.

2. A process according to claim 1 wherein before, during or after the mixing of the active ingredient with the water soluble polydextrose, the polydextrose is also mixed with at least one of a digestible C8-C50 substituted or unsubstituted hydrocarbon and a polyalkylene glycol.

3. A process according to claim 2 wherein the hydrocarbon comprises a C12-C36 fatty alcohol.

4. A process according to claim 3 wherein the hydrocarbon comprises a C14-C22 fatty alcohol.

5. A process according to claim 4 wherein the hydrocarbon comprises cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol.

6. A process according to claim 2 wherein the polyalkylene glycol comprises polyethylene glycol.

7. A process according to claim 1 wherein before, during or after the mixing of the active ingredient with the water soluble polydextrose, the polydextrose is also mixed with a cellulose ether.

8. A process according to claim 7 wherein the cellulose ether comprises at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose.

9. A process according to claim 1 wherein the active ingredient comprises theophylline, metoclopramide or naproxen.

10. A process for the preparation of a solid, controlled release, pharmaceutical composition, in unit dosage form, for oral administration, comprising granulating an active ingredient with a water soluble polydextrose to form granules and compressing the granules to give an oral, solid unit dosage form containing a predetermined, therapeutically active, quantity of the active ingredient.

11. A process for the preparation of a solid, controlled release, pharmaceutical composition in the form of a capsule comprising pelletising, spheronising or granulating an active ingredient with a water soluble polydextrose to form pellets, spheroids or granules and encapsulating the pellets, spheroids or granules to give a capsule containing a predetermined, therapeutically active, quantity of the active ingredient.

12. A process for the preparation of a matrix for admixture with an active ingredient to form a controlled release pharmaceutical composition comprising mixing a water soluble polydextrose with at least one of a digestible, C8-C50 substituted or unsubstituted hydrocarbon and a polyalkylene glycol to form a controlled release matrix.

13. A process according to claim 12 wherein the hydrocarbon comprises a C12-36 fatty alcohol.

14. A process according to claim 13 wherein the hydrocarbon comprises a C14-C22 fatty alcohol.

15. A process according to claim 14 wherein the hydrocarbon comprises cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol.

16. A process according to claim 12 wherein the polyalkylene glycol comprises polyethylene glycol.

17. A solid, controlled release, pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water-soluble polydextrose.

18. A composition according to claim 17 wherein also comprising at least one of a digestible C8-C50 substituted or unsubstituted hydrocarbon and a polyalkylene glycol.

19. A composition according to claim 18 wherein the hydrocarbon comprises a C12-C36 fatty alcohol.

20. A composition according to claim 19 wherein the hydrocarbon comprises a C14-C22 fatty alcohol.

21. A composition according to claim 20 wherein the hydrocarbon comprises cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol.

22. A composition according to claim 18 wherein the polyalkylene glycol comprises polyethylene glycol.

23. A composition according to claim 17 further comprising a cellulose ether.

24. A composition according to claim 23 wherein the cellulose ether comprises at least one of a hydroxyalkylcellulose and a carboxyalkylcellulose.

25. A composition according to claim 17 wherein the active ingredient comprises theophylline, metoclopramide or naproxen.

26. A solid, controlled release, pharmaceutical composition, in unit dosage for, for oral administration, comprising an active ingredient with a water soluble polydextrose in the form of compressed granules containing a predetermined, therapeutically active, quantity of the active ingredient.

27. A solid, controlled release, pharmaceutical composition in the form of a capsule comprising an active ingredient with a water soluble polydextrose in the form of encapsulated pellets, spheroids or granules containing a predetermined, therapeutically active, quantity of the active ingredient.

28. A matrix for admixture with an active ingredient to form a controlled release pharmaceutical composition comprising a water soluble polydextrose and at least one of a digestible C8-50 substituted or unsubstituted hydrocarbon and a polyalkylene glycol.

29. A matrix according to claim 28 wherein the hydrocarbon comprises a C12-36 fatty alcohol

30. A matrix according to claim 29 wherein the hydrocarbon comprises a C14-C22 fatty alcohol.

31. A matrix according to claim 30 wherein the hydrocarbon comprises cetyl alcohol, stearyl alcohol, cetostearyl alcohol or myristyl alcohol.

32. A matrix according to claim 28 wherein the polyalkylene glycol comprises polyethylene glycol.