AU668174B2 - Sustained release pharmaceutical composition - Google Patents

Description

AUSTRALIAt 668174 Patents Act V 7 4 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: i:: Name of Applicant: F.H. Faulding Co. Limited Actual Inventor(s): Angelo Mario Morella Mark Christopher Fisher Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION Our Ref: 333772 POF Code: 89896/23400 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1-

-JA-

The present invention relates to a sustained release pharmaceutical composition, in particular a sustained release pharmaceutical composition including an active ingredient of high solubility in water, and to a method of preparing same.

As is known in the prior art, it is desirable in the treatment of a number of diseases, both therapeuticallyand prophylactically to provide the active pharmaceutical ingredient in a sustained release form.

Desirably the sustained release provides a generally constant rate of release over an extended period. Whilst there is known in the prior art numerous sustained release formulations, the extension of sustained release regimens to active pharmaceutical ingredients of high solubility in water has been extremely limited. It has been found in the prior art that the high solubility in water of the active ingredient tends to generate a product which is susceptible to the phenomenon known as "dose dumping".

That is, release of the active ingredient is delayed for a S 20 time but once release begins the rate of release is very high. Moreover, fluctuations tend to occur in the plasma concentrations of active ingredient which increases the likelihood of toxicity. Further, some degree of diurnal variation in plasma concentration of active ingredient has also been noted.

Prior art preparations may also suffer from other disadvantages, for example bioavailability of prior art preparations may be compromised by food. This is important since complex dosage regimens may lead to non-compliance.

For example, typical highly water soluble active ingredients include the opioid drugs which still play a major role in the treatment of acute and chronic pain, particularly pain associated with terminal diseases such as cancer.

Morphine is regarded as the opioid drug of choice in the treatment of cancer pain. It is universally acknowledged that the oral route of administration is preferred if sufficient pain relief can be obtained with 2 an acceptable profile of side effects with respect to incidence and severity. Until recently, the liquid or immediate release tablet formulations of morphine were the only dosage forms available to physicians for oral administration in the treatment of cancer pain.

The oral administration of morphine has had many critics in the prior art who point to a supposed lack of efficacy. However, the accumulated evidence, particularly from the hospice environment, indicates that this criticism is unfounded if the dose and dosing interval are specifically optimised for each patient, the morphine doses are administered before the pain returns and in a strictly regular regimen. In practical terms, this means morphine doses ranging from 10 mg to in excess of 500 mg with dosing intervals ranging from every 2 to 6 hours. A relationship between blood morphine concentration and pain relief has been established in the treatment of post-operative and cancer pain.

The studies propose that there is a minimum effective concentration (MEC) for morphine for each patient. There is a five-fold interpatient variation in MEC in the treatment of post-operative pain and an even greater variation for cancer pain. This concept of a MEC for opioids has also been demonstrated for pethidine, methadone, fentanyl and ketobemidone. Repeated oral or parenteral doses produce fluctuating blood opioid concentrations, with the peak concentrations sometimes resulting in side effects, while the trough concentrations are usually associated with inadequate pain relief.

Therefore, a formulation of morphine which reduces the fluctuations in blood opioid concentrations and has a longer duration of pain relief a sustained release preparation) has widespread potential to improve pain relief in terminal care.

Currently, there is only one such preparation (MST Continus or MS Contin) being marketed world-wide.

However, the combined pharmacokinetic and pharmacodynamic data suggest that this product is actually a delayed release formulation with some sustained release 3 characteristics. While the manufacturers recommend a 12 hour dosing interval, extensive clinical experience suggests that an 8 hour interval is more realistic for continuous pain control.

Accordingly, it is an object of the present invention to overcome, or at least alleviate, one or more of the difficulties related to the prior art.

Accordingly, in a first aspect of the present invention there is provided a sustained release pharmaceutical pellet composition including a core element including at least one active ingredient having an aqueous solubility of at least 1 in and a core coating for the core element which is partially soluble at a highly acidic pH, and wherein the active ingredient is available for absorption at a relatively constant rate in the intestine over an extended period of time.

By "sustained release" as used herein we mean release of active ingredient at such a rate that blood levels are maintained within the therapeutic range but below toxic levels over an extended period of time e.g. to 24 hours or greater.

By "bioavailability" as used herein we mean the extent to which the active drug ingredient is absorbed from the drug product and becomes available at the site of drug action.

The active ingredients may be selected from the group consisting of antihistamines, antibiotics, antituberculosis agents, cholinergic agents, antimuscarinics, sympathomimetics, sympatholytic agents, autonomic drugs, iron preparations, haemostatics, cardiac drugs, antihypertensive agents, vasodilators, non-steroidal antiinflammatory agents, opiate agonists, anticonvulsants, tranquilisers, stimulants, barbiturates, sedatives, expectorants, antiemetics, gastrointestinal drugs, heavy metal antagonists, antithyroid agents, genitourinary smooth muscle relaxants and vitamins. The invention is applicable to active ingredients of high 4 solubility whether the solubility characteristics are pH dependent or pH independent.

Examples of active ingredients of high solubility are set out in the table below.

SOLUBILITY

DRUG (AQUEOUS) pKA Antihistamines Azatadine maleate Brompheniramine maleate Carbinoxamine maleate Chlorpheniramine maleate Dexchlorpheniramine maleate Diphenhydramine HC1 Doxylamine succinate Methdilazine HC1 Promethazine Trimeprazine Tartrate Tripelennamine citrate Tripelennamine HC1 Triprolidine HC1 Antibiotics Penicillin V Potassium Cloxacillin sodium Dicloxacillin sodium Nafcillin Sodium Oxacillin Sodium Carbenicillin Indanyl Sodium Oxytetracycline HC1 Tetracycline HC1 Clindamycin Phosphate Clindamycin HC1 Clindamycin Palmitate HC1 Lincomycin HC1 Novobiocin Sodium Nitrofurantoin Sodium Metronidazole hydrochloride very soluble 1 in 5 1 in 1 1 in 4 9.3 3.59, 9.12 8.1 9.2 in 1.1 in 1 in 1 in 2 in 0.6 in 4 in 1 in 1 in 2 5.8, 9.1 9.3 1 in 1.5 1 in 2.5 freely soluble freely soluble 1 in 3.5 freely soluble 1 in 2 1 in 10 1 in 2.5 1 in 2 freely soluble 1 in 1 1 in 5 soluble 3.9, 3.6, 2.7 2.7 2.7 2.8 2.6, 2.7, 3.3 3.3, 7.3, 9.1 3.3, 7.7, 9.7 7.7 7.7 7.6 4.2, 9.1 7.2 1 in 1 2.6 5 I I 4 4 t 1 I Ir+ t 44 1I 44 44441 Antituberculosis Agents Isoniazid 1 in 8 Cholinergic Agents Ambenonium chloride 1 in Bethanecol chloride 1 in 1 Neostigmine bromide 1 in 0.5 Pyridostigmine bromide 1 in 1 Antimuscarinics Anisotropine methylbromide soluble Clidinium bromide soluble Dicyclomine HC1 1 in 20 Glycopyrrolate 1 in Hexocyclium methylsulfate freely soluble 15 Homatropine methylbromide 1 in 6 Hyoscyamine sulphate 2 in 1 Methantheline bromide 1 in Hyoscine hydrobromide 1 in 3 Oxyphenonium bromide freely soluble Propantheline bromide very soluble Tridihexethyl chloride 1 in 3 Sympathomimetics Bitolterol Mesylate Ephedrine 1 in 20 Ephedrine HC1 1 in 3 Ephedrine sulphate 1 in 1 Orciprenaline sulphate 1 in 2 Phenylpropanolamine hydrochloride 1 in 2.5 Pseudoephedrine hydrochloride 1 in 1 Ritodrine hydrochloride 1 in 10 Salbutamol sulphate 1 in 4 Terbutaline sulphate 1 in 4 Sympatholytic Agents Phenoxybenzamine hydrochloride 1 in 25 Miscellaneous Autonomic Drugs 1.8, 3.5, 10.8 12.0 9 9.9 7.6 3.2 9.1 9.6 9.6 9.6 9.0, 10.1, 11.4 9 9.8 9 9.3, 10.3 8.7, 10.0, 11.0 4.4 Nicotine soluble 7.9 6 Iron Preparations Ferrous gluconate Ferrous sulphate Haemostatics Aminocaproic acid Cardiac Drugs Acebutolol HC1 Diltiazem hydrochloride Disopyramide phosphate Flecainide acetate Procainamide hydrochloride Propranolol hydrochloride Quinidine Gluconate Timolol maleate Tocainide hydrochloride Verapamil hydrochloride Antihypertensive Aqents 1 in 1 in 1 in 1.5 1 in 5 freely soluble 1 in 20 1 in 20 1 in 0.25 1 in 20 freely soluble freely soluble freely soluble 1 in 20 Captopril freely sol Clonidine hydrochloride 1 in 13 Hydralazine hydrochloride 1 in 25 Mecamylamine hydrochloride 1 in 5 Metoprolol tartrate very solub Vasodilators Papaverine hydrochloride 1 in 2 Non-Steroidal Antiinflammatorv Agents uble le 4.43, 10.73 9.4 7.7 8.4 9.3 9.23 4.0, 8.6 9 7.8 4-6.5 3.7, 9.8 8.2 7.3 11.2 9.68 6.4 4.15 8.2 8.2 8.2 7.1 8.3 Choline salicylate Magnesium salicylate Meclofenamate sodium Naproxen sodium Tolmetin sodium Opiate Aqonists Codeine HC1 Codeine phosphate Codeine sulphate Dextromoramide tartrate Hydrocodone bitartrate Hydromorphone hydrovery soluble 1 in 13 freely soluble soluble freely soluble 1 in 30 1 in 4 1 in 30 1 in 25 1 in 10 7 chloride Pethidine hydrochloride Methadone hydrochloride Morphine sulphate Propoxyphene hydrochloride Anticonvulsants Phenobarbital sodium Phenytoin sodium Troxidone Ethosuximide Valproate sodium Tranquilizers Acetophenazine maleate Chlorpromazine hydrochloride Fluphenazine hydrochloride Prochlorperazine edisylate Promazine hydrochloride Thioridazine hydrochloride Trifluoroperazine hydrochloride Lithium citrate Molindone hydrochloride Thiothixine hydrochloride Stimulants Benzphetamine hydrochloride Dextroamphetamine sulphate Dextroamphetamine phosphate Diethylpropion hydrochloride Fenfluramine hydrochloride 1 in 3 very soluble 1 in 2 1 in 21 1 in 0.3 1 in 3 soluble 1 in 13 1 in 4.5 1 in 5 1 in 7.41 8.3 4.8 8.2 8.7 8.3 8.0, 9.9 1 in 0.4 1 in 10 9.3 3.9, 8.1 3.7, 8.1 9.4 in 2 in 1 1 in 9 1 in 2 1 in 2 freely soluble 1 in 8 freely soluble 1 in 10 1 in 20 freely soluble 8.1 6.9 6.6 9.9 9.9 1 in 20 9.1 8 Methamphetamine hydrochloride Methylphenidate hydrochloride Phendimetrazine tartrate Phenmetrazine hydrochloride Caffeine citrate Barbiturates Amylobarbitone sodium Butabarbital sodium Secobarbital sodium Sedatives Hydroxyzine hydrochloride Methyprylon Expectorants Potassium Iodide Antiemetics Benzaquinamide hydrochloride Metoclopramide HC1 Trimethobenzamide hydrochloride GI Drugs Ranitidine hydrochloride Heavy Metal Antagonists Penicillamine Penicillamine HC1 Antithyroid Agents 1 in 2 freely soluble freely soluble 1 in 0.4 1 in 4 1 in 1 freely soluble 1 in 3 8.8 7.6 8.4 14 7.8 7.9 2.6, 12 1 in 0.7 10 0.7 5.9 7.3, 1 in 2 1 in 2 8.3 8.2, 2.7 1.8 8.0, 10.8 Methimazole 1 in Genitourinary Smooth Muscle Relaxants Flavoxate hydrochloride Oxybutynin hydrochloride Vitamins Thiamine hydrochloride Ascorbic acid Unclassified Agents Amantadine hydrochloride Colchicine freely soluble freely soluble 1 in 1 1 in 3 1 in 2.5 1 in 20 6.96 4.8, 4.2, 11.6 10.4 1.7, 12.4 9 Etidronate disodium freely soluble Leucovorin calcium very soluble 3.1, 4.8 10.4 Methylene blue 1 in 25 -1 Potassium chloride 1 in 3 Pralidoxime chloride 1 in 2 8 In the following description the active ingredient will be illustrated by -eference to the opioid drug, morphine. However, this is illustrative only and the invention is in no way restricted thereto. Preferably, the active ingredient is an opiate selected from the group consisting oZ the salts of codeine, dextromoramide, hydrocodone, hydromorphine, pethidine, methadone, morphine and propoxyphene.

Morphine acts as an agonist primarily at mu, kappa and perhaps delta receptors in the central nervous system. By acting on these receptors the following pharmacological effects are seen. Analgesia due to a central action on pain perception, together with a modulatory effect on the central transmission of noxious sensation. It also causes drowsiness and euphoria (though sometimes dysphoria, particularly in those who are free of pain).

The pharmaceutical pellet composition according to the present invention may include a plurality of coated core elements.

The pharmaceutical composition may be provided in any suitable unit dosage form. An encapsulated form may be used.

The pharmaceutical pellet composition may be provided in a pellet or tableted pellet form. A tablet may be formed by compression of the pellets optionally with the addition of suitable excipients.

In a preferred aspect of the present invention the core coating, in use, generates a dissolution profile for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability to a capsule, tablet or liquid containing an equal amount of the at least one active ingredient in an immediately 10 available form.

"Dissolution profile" as used herein, means a plot of amount of active ingredient released as a function of time. The dissolution profile may be measured utilising the Drug Release Test (724) which incorporates standard test USPXXII 1990. (Test(711)). A profile is characterised by the test conditions selected. Thus the dissolution profile may be generated at a preselected shaft speed, temperature and pH of the dissolution media.

A first dissolution profile may be measured at a pH level approximating that of the stomach. At least a second dissolution profile may be measured at pH levels approximating that of at least ine point in the intestine.

A highly acidic pH may simulate the stomach and a less acidic to basic pH may simulate the intestine. By the term "highly acidic pH" as used herein we mean a pH in the range of approximately 1 to 4. By the term "less acidic to basic pH" we mean a pH of greater than 4 up to approximately 7.5, preferably approximately 6 to A pH of approximately 1.2 may be used to simulate the pH of the stomach.

A pH of approximately 6.0 to 7.5 preferably may be used to simulate the pH of the intestine.

Accordingly in a further preferred aspect, a first dissolution profile is measured at a pH level approximating that of the stomach and a second dissolution profile is measured at a pH level approximating that of at least one point in the intestine; the first and second dissolution profiles for the sustained release composition each being equal to or greater than the minimum dissolution required to provide substantially equivalent bioavailability to a capsule, tablet or liquid containing the at least one active ingredient in an immediately available form.

More preferably, the composition, in use, exhibits less fluctuations in plasma concentrations in active ingredient at steady state over a 24 hour period, relative to the active ingredient in an uncoated form and/or exhibits less diurnal variation in plasma concentration of II active ingredient relative to known capsules rr tablets containing the at least one active ingre. ent in a sustained release form.

For example, dissolution profiles have been generated which exhibit bioavailability substantially equivalent to, or better than, commercially known morphine compcsitions including MS Contin, MST Continus and morphine solution Accordingly, in a preferred aspect of the present invention there is provided a sustained release pharmaceutical pellet composition including a core element including a morphine compound; and a core coating for the core element which is

I,,

partially soluble at a highly acidic pH and wherein the morphine compound is available for absorption at a relatively constant rate in the intestine over an extended .period of time, such that blood levels of morphine are maintained within the therapeutic range over an extended period of time.

It will be understood that further since the morphine compound is provided in a sustained release pellet form significantly less fluctuations in plasma concentrations of active ingredients at steady state over a 24 hour period are encountered, and may allow for less frequent dosing relative to the active ingredient in an uncoated form. This is expected to result in less toxic and more effective therapeutic activity.

Similarly, it has been found that the pharmaceutical pellet composition according to the present invention exhibits less diurnal variation in plasma concentrations of active ingredient than prior art preparations, for example when administered on a two, three or four times daily dosage regimen.

Moreover, the pharmaceutical pellet composition according to the present invention shows no evidence of dose dumping. The relative bioavailability of the active ingredient generated from the pharmaceutical pellet composition is not compromised by food so that compliance will improve as the product may be taken without regard to 12 meals.

Moreover, since the core coating is partially soluble at an acidic pH, for example as encountered in the stomach of the patients, some slow release of active ingredient will occur in the stomach. The slow rate of release of active ingredient may also be at a relatively constant rate.

The active ingredient may be available for absorption even in regions of the gastrointestinal tract which are not sufficiently alkaline to dissolve the enteric core coating component.

Thus the active ingredient is available for absorption in an absorption region substantially 1 immediately after the pyloric sphincter in the patient.

Such an 'absorption region may generally be characterised by a pH between approximately 1.2 and 5.5. Absorption will occur in the small intestine but since absorption will continue over an extended period of time, thus some 2, absorption will occur additionally some way into the large intestine.

Where the active ingredient is a morphine compound, the morphine compound may take any suitable form. The morphine compound may be present in an anhydrous or hydrous form. The morphine compound may be provided in a salt form, e.g. as follows Compound Aqueous Solubility Morphine acetate 1 in 2.25 Morphine lactate 1 in Morphine meconate 1 in Morphine nitrate 1 in Morphine minobasic phosphati 1 in Morphine tartrate 1 in 11 Morphine valerate 1 in Morphine hydrobromide 1 in Morphine hydrochloride 1 in 17.5 Morphine sulphate is also preferred. Morphine sulphate pentahydrate is particularly preferred.

Advantages of the sustained release pharmaceutical pellet composition according to the present invention may 13 thus be summarised as follows The time during which morphine blood levels at steady state are greater than or equivalent to of maximum blood levels (t>0.75Cmax) may be approximately 3.5 hours or greater (t>0.75C max for MS Contin has been reported to be is hours).

(ii) peak to trough variations in blood morphine concentrations at steady state will be between 60-100% (these variations for MS Contin have been reported to be are approximately 300% and for Morphine Solution 4 hourly are approximately 200%) (iii) diurnal variations may be reduced (iv) the co-administration of food will not significantly decrease the extent of morphine absorption or alter the rate of morphine absorption when compared with administration in the fasted state the effect of food on morphine absorption from MS Contin is not known) inter- and intra-subject variation in blood morphine pharmacokinetics may be reduced.

Accordingly in a preferred aspect of the present invention there is provided a sustained release oral pellet composition of a morphine compound for the treatment of pain-associated conditions over an extended period of time following administration, wherein, in vivo, the time during which morphine blood levels at steady state are greater than 75% of maximum blood levels (t>0.75Cmax) is approximately 3.5 hours or greater.

Preferably the t>0.75C is approximately 3.75 to 15 hours or greater, more preferably approximately 6 to hours.

Desirably the pellet composition, in use, generates a dissolution profile as hereinbefore defined for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability as hereinbefore defined to a capsule, tablet or liquid containing an equal amount of the morphine compound in an 14 immediately available form.

In a further preferred aspect there is provided a sustained release oral pellet composition of a morphine compound for the treatment of pain-associated conditions over an extended period of time following administration, wherein, in vivo, the time to reach peak blood concentrations (tmax) is 4.5 hours or greater, preferably from 4.5 to 7.6 hours or greater.

More preferably tue pellet composition, in use, generates a dissolution profile as hereinbefore defined for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability as hereinbefore defined to a capsule, tablet or liquid containing an equal amount of the morphine compound in an immediately available form.

In a still further preferred aspect of the present invention there is provided a sustained release pharmaceutical pellet composition for administration to a S 20 patient at a predetermined dosage and interval which comprises a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and a coating on said core element which comprises the following components: at least 35% by weight of a matrix polymer which is insoluble independent of pH; from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, but which is soluble at a pH of from 6 to from 1 to 60% of an acid-soluble compound soluble at a pH of from 1 to 4, sufficient to provide a slow rate of release of the active ingredient in the stomach; said percentages being weight based on the total weight of components and the ratio of the components and in said coating being effective such that the active ingredient is available for absorption at a relatively constant rate of release in the intestine such that the composition delivers to the patient a 15 therapeutically effective amount of said active ingredient over the course of said predetermined interval, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level for more than 3 hours and so that the time at which the active ingredient reaches its maximum concentration is between about 2 and about 30 hours.

SPreferably the active ingredient is an opiate -A t selected from the group consisting of the salts of codeine, dextromoramide, hydrocodone, hydromorphine, pethidine, methadone, morphine and propoxyphene.

More preferably the active ingredient is a morphine compound.

The rate of dissolution at -highly acidic pH of the core coating will depend on the amount of the partially acid soluble component, the pH dependent and pH independent polymers, and the thickness of the coating.

Typical core coatings may be in the range of approximately to 200 um, preferably approximately 25 to 50 um. It will be understood, accordingly, that the rate of absorption may be modified by modifying the thickness and/or the composition of the core coating.

It has been found that the dissolution rate of the soluble drug at various pH's can be modified at will by altering the ratio of polymers. The ternary system of polymers according to the present invention allows greater flexibility than as known in prior art using only binary systems of polymers.

The enteric polymer may be selected from cellulose acetate phthalate, hydroxypropyl methyl- cellulose phthalate (HPMCP), polyvinyl acetate phthalate, methacrylic acid copolymer, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate and mixtures thereof. Particularly preferred enteric polymers include synthetic resin bearing carboxyl groups.

The methacrylic acid: acrylic acid ethylester 1:1 copolymer sold under the trade designation "Eudragit L100-55" has been found to be suitable.

y?/K The enteric polymer may be present in the coating 16 in an amount of from approximately 1 to 60% by weight, preferably 2 to 20% by weight, more preferably 5 to 15% by weight, based on the total weight of the core coating excluding weight of filler and plasticiser.

The partially acid-soluble component may be selected from polymers such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol and monomers therefor such as sugars, salts, or organic acids and mixtures thereof.

The partially acid-soluble component may be present in the coating in amounts of from approximately 1 to 60%, preferably 15 to 40% by weight, more preferably to 35% by weight, based on the total weight of the core coating excluding weight of filler and plasticiser.

The insoluble matrix polymer may be any suitable pharmaceutically acceptable polymer substantially insoluble independent of pH. The polymer may be selected from ethylcellulose, acrylic and/or methacrylic ester polymers or mixtures thereof and the like may be used.

Polymers or copolymers of acrylates or methacrylates having a low quaternary ammoniu=. content may be used. The acrylic acid ethyl ester: methacrylic acid methyl ester copolymer has been found to be suitable.

The insoluble matrix polymer may be present in the coating in an amount of from approximately 1 to 85% by weight preferably 35 to 75% by weight, more preferably to 65% by weight, based on the total weight of the core coating excluding weight of filler and plasticiser.

The core coating may further include at least one plasticiser; and optionally at least one filler.

Accordingly in a preferred aspect the core coating includes 0 to approximately 50% by weight, preferably to 30% by weight, based on the total weight of the core coating of at least one plasticiser selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol and

I

17 glycerol and the like; and 0 to approximately 75% by weight based on the total weight of the core coating of a filler selected from insoluble materials such as silicon dioxide, titanium dioxide, talc, alumina, starch, kaolin, polacrilin potassium, powdered cellulose, and microcrystalline cellulose and mixtures thereof.

The plasticiser may be selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol and glycerol and the like. It will be understood that the plasticiser used may be largely dictated by the polymer used in the coating formulation, and the compatibility of "the plasticiser with coating solution or dispersion. It should be noted that acid or water soluble plasticisers can also be used to function as the partially acid soluble component. The plasticiser may function to improve the physical stability of the core coating. A plasticiser is particularly preferred where the polymer has a high glass transition temperature and/or is of a relatively low molecular weight.

The plasticiser may be present in any suitable effective amount. Amounts of from approximately 0 to by weight preferably 2.5 to 30% by weight based on the total weight of the core coating, have been fouid to be suitable.

The filler may be present in any suitable effective amount. Amounts of from 0 to approximately by weight, preferably 15 to 60% by weight, more preferably 25 to 45% by weight, based on the total weight of the core coating have been found to be suitable.

Accordingly in a further preferred aspect the core coating has a formulation 18 Ethylcellulose 45 to 60% excluding Methacrylic acid plasticiser acrylic acid ethyl ester and filler 1i:1 copolymer 5 to 15% Polyethylene glycol 20 to 35% Diethyl phthalate 2.5 to Talc 25 to 45% of total weight of core coating The active ingredient may be present in the core element in any suitable effective amount. The amount of active ingredient is dependent on the potency of the active ingredient and on the desired dosage strength and volume of a unit dose of the drug product. The active ingredient may be present in amounts of approximately 0.1 to 95% by weight, based on the total weight of the core element. The active ingredient may preferably be a S' morphine compound. The morphine compound may be present in amounts of approximately 10 to 60% by weight, based on the total weight of the core element. The binding agent may be present in amounts of from approximately 0.1 to by weight preferably approximately 0.1 to 20% by weight based on the total weight of the core element.

The binding agent may be of any suitable type.

Suitable binders may be selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, sugars and mixtures thereof. The binding agent may be provided in the form of a granulating solution. An aqueous or organic solvent may be included. Methanol, ethanol or mixtures thereof may be used as solvents.

The size and amount of the core seed may vary substantially from approximately 100 um to 1700 um depending upon the amount of active ingredient to be included. Accordingly, the core seeds may vary from approximately 5 to 99% by weight, preferably 40 to 90% by weight based on the total weight of the core element, depending on the potency of the active ingredient. The core seed may be of such a diameter to provide a final core element having a diameter of approximately 200 to 2000 um.

19 The core seed may be of any suitable type. A sugar seed or an active core seed may be used.

The core element may further include other carriers or excipients, fillers, stabilizing agents and colorants. Suitable fillers may be selected from insoluble materials such as silicon dioxide, talc, titanium dioxide, alumina, starch, kaolin, polacrilin potassium, powdered cellulose, and microcrystalline cellulose and mixtures thereof. Soluble fillers may be selected from mannitol, sucrose, lactose, dextrose, sodium chloride, sorbitol and mixtures thereof.

In a preferred aspect the core element includes an effective amount of at least one morphine compound; 1 optionally at least one core seed; and at least one binding agent.

The core element may have a formulation Morphine sulphate 10 to 60% by weight Core seeds 30 to 89.9% by weight Hydroxypropylmethylcellulose 0.1 to 10% by weight Alternatively the core element may have a formulation Morphine sulphate 10 to 60% by weight Core seeds 30 to 87.5% by weight Polyvinyl pyrrolidone 2.5 to 10% by weight The core coating composition may be provided in the form of a solution, dispersion or suspension.

In the form of a solution, the solvent may be present in amounts of from approximately 25 to 97% by weight, preferably 85 97%, based on the total weight of the core coating composition. The solvent for the polymer may be a solvent such as water, methanol, ethanol, methylene chloride and mixtures thereof.

In the form of a dispension or suspension, the diluting medium may be present in amounts of from approximately 25 to 97% by weight, preferably 75 97%, based on the total weight of the core coating composition and is comprised predominantly of water.

20 Typical core coating formulations may be prepared in the amounts as follows: Core Coatin- Formulation A. Insoluble matrix polymer 45 65% excluding Enteric polymer 4 10% solvent and filler Acid soluble polymer 15 35% Plasticiser 4 30% Solvent 85 97% of total coating formula.

B. Insoluble matrix polymer 45 65% excluding Enteric polymer 4 15% solvent and filler Acid soluble polymer 15 Plasticiser 4 30% Diluting medium 75 97% of total coating formula Optionally, an amount of filler not exceeding of the core coating formulations weight excluding solvent, may be added. The coated pellet may be manufactured 2 utilising standard techniques, for example as described in Australian Patent 617,573, the entire disclosure of which is incorporated herein by reference.

The sustained release pharmaceutical pellet Scomposition may be administered under a similar dosage regimen to that used in the prior art. The multi-pellet encapsulated form may for example be administered every eight to twenty-four hours in sustained release form.

In a further preferred aspect of the present invention the pharmaceutical pellet composition incorporating morphine compound may provide effective pain relief with twice or three times or four times daily administration. Versatility of dosing may be achieved with 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 500 mg or any other dose strength of capsules required.

The pharmaceutical pellet composition may be in multi-pellet encapsulated, sprinkle sachet or tableted forms.

In accordance with a further aspect of the present invention, there is provided a method of treating painassociated conditions in patients requiring such treatment -21which method includes administering to a patient wan effective amount of a sustained release pharmaceutical pellet composition including a core element including at least one morphine compound having an aqueous solubility of at least 1 in 30; and a core coating for the core element which is partially soluble at a highly acidic pH and wherein the morphine compound is available for absorption at a relatively constant rate in the intestine over an extended period of time, such that blood levels of morphine are maintained within the therapeutic range over an extended period of time.

The method of treatment according to this aspect of the present invention is particularly applicable to the treatment of acute and chronic pain, particularly pain associated with terminal disease such as cancer and chronic backpain, as well as post-operative pain.

a Preferable the pharmaceutical sustained release composition is provided in a unit dosage form and administration occurs at intervals of approximately 8 to 24 hours.

The present invention will now be more fully described with reference to a i ithe accompanying examples and figures in which: Figure 1 is an in-vitro dissolution profile at pH 1.2 of morphine sulphate in formulation 1; Figure 2 is an in-vitro dissolution profile at pH 7.5 of morphine sulphate in formulation 1; Figure 3 is an in-vitro dissolution profile at pH 1.2 of morphine sulphate in formulation 2; Figure 4 is an in-vitro dissolution profile at pH 7.5 of morphine sulphate in formulation 2; Figure 5 is an in-vitro dissolution profile at pH 1.2 of morphine sulphate in formulation 3; Figure 6 is an in-vitro dissolution profile at pH 7.5 of morphine sulphate in formulation 3; Figure 7 is a profile of morphine concentration in blood versus time of morphine solution versus formulation 3; SC C:\WVIVORDSIIMONE'ODELEth164CJIC93.D La -21a- Figure 8 displays morphine plasma levels showing lead-in period; and Figure 9 is an expansion of the figure 8 from 0-12 hours.

It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction on the generality of the invention specified below.

EXAMPLE 1 1. Formulation 1 Core Composition 1 Morphine Sulphate pentahydrate 194 g Core seeds (sugar seeds) 170 g Polyvinyl pyrrolidone 37 g Ethanol 185 g Hybrid Core Coating Composition 1 Polyethylene Gylcol 12 g Ethylcellulose 25 g Diethyl phthalate 2g o SC C:\WINWORD\SIMONENODELETE416iS4C93.DOC 22 Methacrylic acid acrylic acid ethyl ester 1:1 copolymer 5 g Talc 22 g Ethanol 667 g 2. Formulation 2 Core Composition 2 Morphine Sulphate pentahydrate 194 g Core Seeds (sugar seeds) 170 g Polyvinyl pyrrolidone 37 g Ethanol 185 g Hybrid Core Coating Composition 2 Polyethylene Glycol 25 g Ethylcellulose 41 g Diethyl phthalate 3 g Methacrylic acid: acrylic acid ethyl ester 1:1 copolymer 4 g Talc 37 g Ethanol 1106 g 3. Formulation 3 Core Composition 3 Morphine Sulphate Pentahydrate 364 g Core Seeds (sugar seeds) 733 g Hydroxypropylmethylcellulose 14 g Ethanol 986 g Hybrt Core Coating Composition 3 Polyethylene Glycol 47 g Ethylcellulose 90 g Diethyl phthalate 19 g Methccrylic acid acrylic acid ethyl ester 1:1 copolymer 20 g Talc 88 g Ethanol 2509 g 4. Formulation 4 Core Composition 4 Morphine Sulphate Pentahydrate 1796 g Core Seeds (sugar seeds) 6167 g Hydroxypropylmethylcellulose 90 g Core Coating Composition 4 Ethylcellulose 644 g Dll~slar~ 23 Polyethylene Glycol 230 g Eudragit L100-55 187 g Diethyl Phthalate 131 g Talc 625 g Spheronised Core Manufacture (Core Composition 1 and 2) The core seeds were placed in a spheroniser. The core seeds were then coated with a dry mixture of the active ingredients and inactive excipients whilst concomittantly adding a solution of the binder components.

The wet cores so formed were then dried in a fluidised bed dryer for 1 hour.

Rotacoating Core Manufacture (Core Compositions 3 and 4) The core seeds were placed in a rotor fluid bed machine. The core seeds were then coated with a 15 suspension or solution of the active ingredients and inactive excipients including at least one binding agent, in a suitable liquid. The wet cores so formed were then dried in a suitable drier for one hour.

Pellet Manufacture 20 The dried spheronised cores 1 and 2 were then placed in a fluid bed coating apparatus. The hybrid core coating compositions 1 and 2 were then sprayed onto the cores 1 and 2 to form Formulation 1 and 2 pellets respectively. At the conclusion of the process, the pellets were fluid bed dried.

The dried cores 3 and 4 were then placed in a rotary fluid bed or conventional fluid bed coating apparatus. The hybrid core coating compositions 3 and 4 was then sprayed onto the cores 3 and 4 to form Formulation 3 pellets.

A dissolution test was conducted on the pellet compositions 1, 2 and 3 utilising the test method USPXXII 1990 (Test 711). A sample is dissolved in an aqueous medium previously degassed and equilibrated to 370C.

The media are USP pH 1.2 media without enzymes and pH phosphate buffer. A sample of known volume is withdrawn at designated time intervals from the bath as directed and subjected to a suitable assay procedure. The mg of morphine sulphate as a function of time is plotted as the 24 dissolution profile.

The tests were conducted at pH 1.2 and pH The baskets containing the samples were rotated at approximately 50 r.p.m. and the aqueous medium maintained at approximately 37°C.

The results are given in Tables 1 to 6 and Figures 1 to 6 herein. The results for Formulation 1 at pH 1.2 and 7.5 are given in Tables 1 and 2 respectively. The hybrid coating on Formulation 1 pellet allows dissolution at pH 1.2, a significantly faster rate of dissolution is observed at pH 7.5. The results for Formulation 2 pellet at pH 1.2 and 7.5 are given in Tables 3 and 4 respectively, and are similar to those obtained from composition A.

S, 15 The results for Formulation 3 pellets are similar to those achieved for Formulation 1 at pH 7.5. The asults achieved for Formulation 3, however, illustrate a significant prolongation of release thereover.

TABLE 1 20 DISSOLUTION DATA FOR FORMULATION 1 AT PH 1.2 (AVERAGED DATA FOR 3 SAMPLES) TIME MIN. MG RELEASED SD RELEASED SD 0.00 0.00 0.00 0.00 *i 60 2.29 0.09 4.04 0.15 120 8.43 0.18 14.88 0.28 180 14.66 0.39 25.87 0.71 TABLE 2 DISSOLUTION DATA FOR FORMULATION 1 AT PH 7.5 (AVERAGED DATA FOR 3 SAMPLESI TIME MIN. MG RELEASED SD RELEASED SD 1.85 0.09 3.28 0.17 9.03 0.25 16.07 0.45 120 23.20 0.42 41.29 0.77 180 35.39 0.50 63.00 1.01 25 1 4 TABLE 3 DISSOLUTION DATA FOR FORMULATION 2 AT pH 1.2 (AVERAGED DATA FOR 3 SAMPLES) TIME M..L'L MG RELEASED SD RELEASED SD 1.64 0.00 3.22 0.01 6.26 0.09 12.25 0.16 120 20.24 0.18 39.63 0.46 180 36.39 0.27 71.27 0.72 240 47.47 0.49 92.97 1.12 TABLE 4 DISSOLUTION DATA FOR FORMULATION 2 AT PH 7.5 (AVERAGED DATA FOR 3 SAMPLES) TIME MIN. MG RELEASED SD RELEASED SD 2.63 0.00 5.12 0.03 60 8.69 0.09 16.94 0.11 120 21.62 0.33 42.13 0.40 180 33.66 0.59 65.60 0.79 240 42.47 0.82 82.78 1.13 TABLE DISSOLUTION DATA FOR FORMULATION 3 AT PH 1.2 (AVERAGED DATA FOR 3 SAMPLES) TIME MIN. MG RELEASED SD %-RELEASED SD 1.44 0.39 2.12 0.53 3.03 0.33 4.48 0.39 120 6.78 0.30 10.03 0.36 180 10.17 0.18 15.04 0.34 240 13.87 0.41 20.51 0.29 300 17.45 0.31 25.81 0.30 360 21.29 0.21 31.49 0.27 420 24.75 0.32 36.62 0.46 480 28.60 0.64 42.30 0.37 540 32.63 0.42 48.28 0.45 600 35.80 0.92 52.95 0.37 24 hours 67.60 1.26 100.04 3.79 26 TABLE 6 DISSOLUTION DATA FOR FORMULATION 3 AT pH 7.5 (AVERAGED DATA FOR 3 SAMPLES) TIME MIN. MG RELEASED SD RELEASED SD 30 2.19 0.11 3.23 0.17 7.05 0.89 10.38 1.26 120 18.07 1.05 26.63 1.44 180 28.12 1.03 41.44 1.35 240 37.86 1.05 55.80 1.32 300 47.60 1.48 70.16 1.96 360 56.33 0.54 83.03 0.47 420 63.03 2.01 92.90 2.76 480 65.97 0.61 97.23 0.75 540 69.13 0.41 101.89 0.79 600 70.20 0.43 103.47 0.45 24 hours 74.76 2.36 110.19 3.04 SD Standard Deviation EXAMPLE 2 20 Two sustained release morphine compositions in I: accordance with the present invention have been trialled in patients with back pain (fed and fasting) and in healthy volunteers (fasting). The results of these trials suggest that Faulding already has a product that is superior to a commercial product MS Contin with regard to sustained delivery of morphine. An investigation has also :been initiated into understanding the effect that food has on the absorption of morphine.

The sustained release oral morphine compositions according to the present invention are designated Formulation 1 and Formulation 2.

1. PART A A single dose 3 way crossover study under fasted conditions was conducted in six patients suffering chronic pain. On 3 occasions separated by one week, patients received a 50 mg oral morphine dose as either a solution (reference dose) or one of two sustained release formulations as pellets contained within a capsule (designated Formulation 1, a pH dependent release 27 formulation; and Formulation 2, a pH independent release formulation). The doses were administered after an overnight fast. Venous blood samples were taken at specified time intervals from immediately after dose administration for 30 hours after the sustained release formulations and for 10 hours after the reference solution dose. The morphine concentration in the blood samples was quantitated using high pressure liquid chromatography (HPLC) with electrochemical detection. Table 3.1 summarises the mean area under the curve (AUC); Cma x (maximum blood concentration); Tmax (time to reach peak blood concentration); T 1 /2 (apparent terminal half life); T >0.75 Cmax (time for which blood concentration was greater than 75% of Cm) and relative bioavailability The results revealed that both Formulation 1 and Formulation 2 provide a sustained release relative to the reference solution as assessed by: a lower Cmax for the formulations; 1 20 a longer Tma x for the formulations; and a longer time for which the blood morphine concentration was above 0.75 C for the max formulations.

There was a significant decrease in C values max for each formulation compared with the reference solution.

The mean Cm x for the solution was 73.6±30.9 ng/mL whe'reas the corresponding values for Formulations 1 ard 2 were 21.6+7.1 ng/mL and 23.2+4.8 ng/mL respectively. The variability in Cmax for Formulations 1 and 2 as demonstrated by the coefficient of variation was significantly less than that of the solution in the same patients.

There was a significant increase in T values max for the formulations relative to that obtained with the reference solution. The mean T for solution max was 1.07+1.09 hours whereas the equivalent values were 5.33±1.2 hours and 4.25±1.33 hours for Formulations 1 and 2 respectively. The variability in T values for the max formulations was less than that obtained for the solution in the same patients.

28 The time the blood morphine concentration was greater than or equal to 0.75 Cma x was significantly greater for the formulations compared to the reference solution dose. The mean time was 190 minutes for Formulation 1 and 237 minutes for Formulation 2 compared to only 59 minutes for the reference solution. Expressing these data as percentage of the time of the reference solution, Formulation 1 was 322% while Formulation 2 has 400% greater time that the blood morphine concentration was greater than 0.75 Cmax compared to the solution.

There was no significant difference between the AUC for the formulations and that obtained for the reference solution (Table 3.1).

The relative bioavailability for the formulations was calculated from the ratio of the AUC for the appropriate formulation relative to that obtained for the reference solution for each patient. The relative bioavailability was 83.5% for Formulation 1 and 102.6% for Formulation 2.

The AUC and relative bioavailability data suggest that the extent of absorption of morphine from the three different formulations is similar whereas the Cmax max' T ma x and T0.

75 Cma x data indicate that the max _07Ca formulations exhibit the typical slower and prolonged absorption of a true sustained release preparation.

29 TABLE 3.1 RESULT OF STUDY PART A PARAMETER SOLUTION FORMULATION 1 FORMULATION 2 MEAN MEAN OBSERVED MEAN OBSERVED DIFF DIFF

AUC

(ng.h/mL)

SD

CV%

max (ng/mL)

SD

CV%

T

max (hours)

SD

CV%

199.77 170.72 -29.05 +66.32 33 73.57 ±30 .92 42 1.07 +1.1 103 +86.3 51 21.60 -52.0 +7.12 33 193.77 +46.35 24 23.16 -50.4 +4.76 21 4.25 3.18 5.33 +1.21 23 4.26 +1.33 31 Bioavailability 100.0 SD +0.00 CV% 0 83.53 -16.47 102.62 2.62 tl/2 (hours)

SD

CV%

T>0.75 Cmax (minutes)

SD

CV%

3.02 +1.97 65 59.0 +37 63 +27.87 33 6.58 +5.33 81 +25.77 3.56 7.65 4.63 +5.59 73 189.8 130.8 237.3 178.3 +76 40 30 2. PART B A single dose 3 way crossover study under fed conditions was conducted in six patients suffering chronic pain. The same patients took part in both Parts A and B of this study. On 3 occasions separated by one week, patients received a 50 mg oral morphine dose as either a solution (reference dose) or one of two sustained release formulations as pellets contained within a capsule (designated Formulation i, a pH dependent release formulation; and Formulation 2, a pH independent release formulation). The doses were administered after an overnight fast. Venous blood samples were taken at specified time intervals from immediately after dose administration for 30 hours after the sustained release formulations and for 10 hours after the reference solution dose. The morphine concentration in the blood samples was quantitated using high pressure liquid chromatography (HPLC) with electrochemical detection. Table 3.2 summarises the mean area under the curve (AUC); Cmax (maximum blood concentration); Tma x (time to reach peak blood concentration); T>0.

75 Cmax (time for which blood concentration was greater than 75% of Cmax) and relative bioavailability The results revealed that, in the presence of food, both Formulation 1 and 2 provide a sustained release relative to the reference solution as assessed by: a lower Cmax for the formulations; a longer Tmax for the formulations; and a longer time for which the blood morphine concentration was above 0.75 Cmax for the max formulations.

There was a significant decrease in Cmax values max for each formulation compared with the reference solution. The mean Cmax for the solution was 80.7 26.4 ng/mL whereas the corresponding values for Formulation 1 and Formulation 2 formulations were 22.0 8.1 ng/mL and 32.6 18.1 ng/mL respectively. The variability in Cmax for Formulations 1 and 2 as demonstrated by the coefficient of variation was similar 31 for all formulations. The C values for each max formulation obtained under fed conditions were similar to the values obtained in the same patients under fasting conditions (Part A).

There was a significant increase in T values for the formulations relative to that obtained with the reference solution. The mean T for solution max was 1.32 1.65 hours whereas the equivalent values were 5.83 0.75 and 4.5 0.84 hours for Formulation 1 and 2 respectively. The variability in Tmax values for the formulations was less than that obtained for the solution. The T values were similar under fed and fasted conditions for each respective formulation.

The time the blood morphine concentration was greater than or equal to 0.75 Cmax was significantly max greater for the formulations compared to the reference solution dose. The mean time was 231.2 minutes for Formulation 1 and 168.5 minutes for Formulation 2 compared to only 52.2 minutes for the reference solution.

Expressing these data as percentage of the time of the reference solution, Formulation 1 was 443% while Formulation 2 has 323% greater time that the blood morphine concentration was greater than 0.75 C max compared to the solution. The data for the time greater than 0.75 Cma x under fed and fasting conditions was ',similar for each respective formulation.

Under fed conditions, there was a significant difference between the AUC for the formulations and that obtained for the reference solution (Table 3.2) the reference solution having a greater AUC than either formulation. The mean areas were very similar for the formulations with mean values of 204.13 106.11 ng.h/mL and 225.09 138.52 ng.h/mL for Formulation 1 and Formulation 2 respectively. The mean AUC for the solution under fed conditions was 281.98 112.58 ng.h/mL. The intersubject variability in AUC was similar for all formulations as shown by the coefficient of 'vriation.

'A comparison of AUC data obtained under fed and fasted conditions shows that the AUC for the reference 32 solution expressed as a ratio of fed/fasted was 1.41 (range 0.94 to 1.9) with all but one patient having a ratio of greater than unity. There was a similar trend with the Formulations in that the mean AUC obtained when the formulations were administered immediately after food were larger than the equivalent value obtained in the fasted state.

The primary concern was to establish that "dose dumping" did not occur with either formulation. The data indicate that the bioavailability of morphine from formulations in the presence of food is at least equivalent to and possibly greater than the bioavailability from the same formulation in the fasted state and that the formulations behave in a similar manner to the solution with regard to the influence of food on the absorption of morphine.

The relative bioavailability for the formulations relative to that obtained for the reference solution was 79.4% for Formulation 1 and 78.2% for Formulation 2.

The AUC and relative bioavailability data suggest that the extent of absorption of morphine from the formulations is similar but slightly less than the solution in the fed state whereas the Cmax Tmax and T 0.75 Cmax data indicate that the formulations exhibit the typical slower and prolonged absorption of a true sustained release preparation.

33 TABLE 3.2 RESULT OF STUDY PART B PARAMETER SOL

M

AUC

(ng.h/mL)

SD

CV%

C

max (ng/ml)

SD

CV%

T

max (hours)

SD

CV%

UTION FORMULATION 1 [EAN MEAN OBSERVED

DIFF

281.98 204.13 -77.85 +112.58 40 +106.11 52 FORMULATION 2 MEAN OBSERVED

DIFF

225.09 -56.89 +138.52 62 32.63 -48.03 +18.07 80.66 22.00 -58.66 +26.44 33 1.32 +1.65 125 Bioavailability 100.0 SD +0.00 CV% 0 +8.05 37 5.83 +0.75 13 79.4 ±47.3 60.0 231.2 +73.9 32 4.51 4.50 +0.84 19 3.18 -20.6 78.2 -21.8

T

T>0.75Cmax (minutes)

SD

CV%

52.2 +39.3 75 179.0 ±27.1 35.0 168.5 +55.5 33 116.3 EXAMPLE 3 A single dose 2-way crossover study was conducted in eight adult patients suffering chronic pain associated with non-terminal disease states. All study doses were taken fasting and food was withheld for the first 12 hours of each study period. The mean data represent data from 8 patients taking reference solution and 9 patients taking 34 Formulation 3 capsule.

On two occasions separated by one week, the volunteers received a 100 mg oial morphine dose administered as either 33.33 mg doses in solution at 0.4 and 8 hours or one sustained release formulation as pellets contained in a capsule (Formulation 3, a pH dependent release formulation). The capsule dose was administered with 200 mL of water and a further 200 mL of fluid was taken at 4 and 8 hours post dose administration, to mirror the fluid intake of the morphine solution dose.

The morphine solution dose (100 mg) was administered as three equal 33.33 mg doses at 0.4 and 8 hours with the total volume of fluid at each dose being 200 mL. Venous blood samples were collected pre-dose and at specified time intervals for 18 hours after the first of the three oral solution doses and for 32 hours following administration of the sustained release formulation. The morphine concentration in the study blood samples was quantitated using high pressure liquid chromatography (HPLC) with electrochemical detection. Table 4.1 summarises the mean area under the concentration versus time curve (AUC) for zero to 18 hours; C (maximum max observed blood concentration); t (time to reach max' maximum observed blood concentration); t>0.75Cmax (time for which maximum observed blood concentration was greater than or equal to 75% of Cmax) and relative max bioavailability The study results indicated that, under fasting conditions, administration of the test product Formulation 3 provided a sustained release relative to the reference solution as assessed by: lower Cmax values for Formulation 3; longer tmax values for Formulation 3; and longer values for the parameter T0.75Cmax for Formulation 3.

There was a significant decrease in the C max values for Formulation 3 compared with the reference solution with mean values of (34.24 12.25) ng/mL and (157.72 59.76) ng/mL for Formulation 3 and solution, 35 respectively. The Cmax value for the solution was taken as three times the Cmax value following the first of the three solution doses. The variability in Cm for max Formulation 3 and solution as demonstrated by the coefficient of variation was minimal for the two products.

There was a significant increase in the t max values for Formulation 3 relative to that obtained following each dose of solution. The mean t max for solution was (0.63 0.23) hours and for Formulation 3 was (7.67 2.06) hours. The variability in ta values max for Formulation 3 was less than that obtained for the solution (27% vs respectfully.

The mean time for which the maximum observed blood concentration was greater than or equal to 0.75 Cm was max 6.25 hours for Formulation 3 suggesting that the product possesses adequate sustained release properties.

There was no significant difference between the AUC (zero to 1.6 hours) values of the reference solution and Formulation 3. (Table 4.1).

The relative bicavailability for Formulation 3 compared to the reference solution was (102.06%) indicating that the extent of absorption of morphine for Formulation 3 is adequate.

The tmax and T>0 75 Cmax values obtained following dosing with Formulation 3 suggest that, under fasting conditions, Formulation 3 possesses improved sustained release properties compared with those of the first prototypes Formulation 1 and Formulation 2. The v'er SuS concentration time profile of the mean data for 330 Formulation so= substantiates thise '7 claim.

Formulation substantiates this claim.

XC

36 TABLE 4.1 RESULT OF FASTING STUDY MEAN DATA PARAMETER SOLUTION FORMULATION MEAN MEAN OBSERVED~

DITFFERENCE

AUC (0-18 h) 374.21 361.03 13.18 (ng.h/mL) SD 155.52 131.94 CV% 42 37 C mx157.72 34.24 -123.48 (ng/rnl) SD 59/76 12.25 CV% 38 36 Tmax 0.63 7.67 7.04 (h) SD 0.23 2.06 CV% 37 27 Bioavailability 100.00 102.06 2.06 SD 00.00 18S47 CV% 0 18 t123.48 5.77 2.29 (h) SD 2.20 3.70 CV% 63 64 T1 0 7 5 Cma NA 6.25 W (h) SD 1.28 CV% NA =not applicable 37 EXAMPLE 4 A randomised, 3-phase, open-label study was conducted to compare the steady state pharmacokinetics of Oral immediate-release morphine sulphate solution; Oral formulation 4 according to the present invention; Oral controll e--release morphine sulphate tablets (MSC Contin a e, Fifty patients who were experiencing moderate to severe stable pain due to cancer entered the study. Of the fifty patients, thirty-four were randomised and twenty-four completed the study. Ten patients were withdrawn after randomisation.

Eligible patients initially received Solution (A) 15 every four hours for at least eight days during a lead-in period. The dosage level was adjusted to provide control of pain and remained at a constant level for the last three days of this period.

During the crossover period, all patients received 20 capsules every 12 hours, Solution every 4 hours and tablets every 12 hours for 7 days in a randomised, crossover fashion. The 24 hour dosage level was the same S' as that which provided adequate pain relief during the last three days of the lead-in period.

Results A B C SCmax (1g/L) 48.3 32.1 42.3 T max(Hr) 0.7 5.7 3.4 AUC (pg-Hr/L) 266 298 272 Cmin(pg/L) 12.4 17.7 9.2 t>0.75 C 9.14 3.12 max *Fluct 1 3.70 0.91 4.27 2 1.73 0.60 1.51 *Fluct 1 is (C max-C min)/C max min mn **Fluct 2 is (C a-C .in)/AV Concentration max mm Figure 8 morphine plasma levels showing lead-in period RA Tigure 9 expansion of Figure :I from 0-12 hours 16 411 QI 38 Conclusions The AUC values for morphine were similar among A, B and C; (ii) The formulation of the current invention exhibited a true sustained release g, i.e. a t>0.75 Cmax of over 9 hours, wfei extremely low fluctuation indices, in contrast to those of the immediate release solution and MSC tablets Finally, it is to be understood that various other modifications and/or alterations may be made without departing from the spirit of the present invention as outlined herein.

Claims (27)

1. A sustained release pharmaceutical pellet composition including a core element including at least one active ingredient having an aqueous solubility of at least 1 in and a core coating for the core element which is partially soluble at a highly acidic pH, and wherein the active ingredient is available for absorption at a relatively constant rate in the intestine over an extended period of time.

2. A sustained release pharmaceutical pellet composition according to claim 1 wherein the active ingredient is an opiate agonist selected from the group consisting of the salt of codeine, dextromoramide, S.'hydrocodone, hydromorphine, pethidine, methadone, morphine and propoxyphene.

3. A sustained release pharmaceutical pellet composition according to claim 2 wherein the active ingredient is a morphine compound.

4. A sustained release pharmaceutical pellet composition according to claim 2, wherein the core coating, in use, generates a dissolution profile as hereinbefore defined for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability as hereinbefore defined to a capsule, tablet or liquid containing an equal amount of the active ingredient in an immediate available form.

5. A sustained release pharmaceutical pellet composition according to claim 4, wherein a first dissolution profile is measured at a pH level approximating that of the stomach and a second dissolution profile is measured at a pH level approximating that of at least one point in the intestine; the first and second dissolution profiles for the sustained release composition each being equal to or greater than the minimum dissolution required to provide substantially equivalent bioavailability to a capsule, tablet or liquid containing 40 an equal amount of the active ingredient in an immediate available form.

6. A sustained release pharmaceutical pellet composition according to claim 5, wherein the composition, in use, exhibits less fluctuations in plasma concentrations of active ingredient at steady state over a 24 hour period, relative to the active ingredient in an uncoated form and/or exhibits less diurnal variation in plasma concentration of active ingredient relative to prior art capsules or tablets containing the active ingredient in a sustained release form.

7. A sustained release pharmaceutical pellet composition for administration to a patient at a :predetermined dosage and interval which comprises a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and a coating on said core element which comprises the following components: at least 35% by weight of a matrix polymer which S 20 is insoluble independent of pH; from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, but which is soluble at a pH of from 6 to from 1 to 60% of an acid-soluble compound soluble at a pH of from 1 to 4, sufficient to provide a slow rate of release of the active ingredient in the stomach; said percentages being weight based on the total weight of components and the ratio of the components and in said coating being effective such that the active ingredient is available for absorption at a relatively constant rate of release in the intestine such that the composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level (t>0.75Cmax) for max approximately 3.5 hours or greater and so that the time at which the active ingredient reaches its maximum 41 concentration (tmax) is 4.5 hours or greater.

8. A sustained release pharmaceutical pellet composition according to claim 7, wherein the active ingredient is an opiate .a*Ie.&t selected from the group consisting of the salts of codeine, dextromoramide, hydrocodone, hydromorphine, pethidine, methadone, morphine and propoxyphene.

9. A sustained release pharmaceutical pellet composition according to claim 8 wherein the active ingredient is a morphine compound.

A sustained release pharmaceutical pellet composition according to claim 9 wherein the coating contains as component ethyl cellulose, acrylic ester polymers, methacrylic ester polymers, an acrylic acid ethyl ester methacrylic acid methylester (1:1) copolymer, or a mixture thereof; as component cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate S 20 phthalate, methacrylic acid:acrylic acid ethylester 1:1 copolymer, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate and mixtures thereof; and as component polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 'polyethylene glycol, polyvinyl alcohol and monomers 4 therefor and mixtures thereof$.

11. A sustained release pharmaceutical pellet composition according to claim 10, wherein the coating includes approximately 35 to 75% by weight of the insoluble matrix polymer; approximately 2 to 30% by weight of the enteric polymer; and approximately 15 to 40% by weight of the partially acid-soluble component.

12. A pharmaceutical sustained release product in a unit dosage form including a plurality of pellets, each pellet including I 42 a core element including at least one active ingredient having an aqueous solubility of at least 1 in and a core coating for the core element which is partially soluble at a highly acidic pH and wherein the active ingredient is available for absorption at a relatively constant rate in the intestine over an extended period of time, such that blood levels of active ingredient are maintained within the therapeutic range over an extended period of time.

13. A sustained release pharmaceutical pellet compositing including a core element including a morphine compound; and a core coating for the core element which is partially soluble at a highly acidic pH and wherein the morphine compound is available for absorption at a relatively constant rate in the intestine over an extended period of time, such that blood levels of morphine are maintained within the therapeutic range over an extended period of time.

14. A sustained release pharmaceutical pellet composition according to claim 13, wherein the morphine ,compound is a morphine sulphate compound.

15. A sustained release pharmaceutical pellet composition according to claim 13, wherein the composition, in use, exhibits less fluctuations in plasma concentrations of the morphine compound at steady state over a 24 hour period, relative to a prior art morphine compound in a sustained release form and/or exhibits less diurnal variation in plasma concentration relative to the prior art morphine compound in a sustained release form.

16. A sustained release oral pellet composition of a morphine compound for the treatment of pain-associated conditions over an extended period of time following administration, wherein, in vivo, the time during which morphine blood levels at steady state are greater than of maximum blood levels (t>0.75Cmax) is approximately hours or greater.

17. A sustained release oral pellet composition 43 according to claim 16, wherein the t>0.75C is max approximately 3.75 to 15 hours or greater.

18. A sustained release oral pellet composition according to claim 17, wherein the t>0.75C is max approximately 6 to 15 hours.

19. A sustained release oral pellet composition according to claim 16 wherein the pellet composition, in use, generates a dissolution profile as hereinbefore defined for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability as hereinbefore defined to a capsule, tablet or liquid containing an equal amount of the morphine compound in an immediately available form.

20. A sustained release oral pellet composition according to claim 19, wherein the composition, in use, exhibits less fluctuations in plasma concentrations of morphine compound at steady state over a 24 hour period, relative to the morphine compound in an uncoated form S 20 and/or exhibits less diurnal variation in plasma concentration relative to prior art cepsules or tablets containing the morphine compound in a sustained release form.

21. A sustained release oral pellet composition of a morphine compound for the treatment of pain-associated conditions over an extended period of time following administration, wherein, in vivo, the time to reach peak blood concentrations (t max) is 4.5 hours or greater. max

22. A sustained release oral pellet composition according to claim 21, wherein the tmax is from 4.5 to max 7.6 hours.

23. A sustained release oral pellet composition according to claim 22, wherein the pellet composition, in use, generates a dissolution profile as hereinbefore defined for the sustained release composition, which is equal to or greater than the minimum dissolution profile required to provide substantially equivalent bioavailability as hereinbefore defined to a capsule, tablet or liquid containing an equal amount of the 44 morphine compound in an immediately available form.

24. A sustained release oral pellet composition according to claim 23, wherein the composition, in use, exhibits less fluctuations in plasma concentrations of morphine compound at steady state over a 24 hour period, relative to the morphine compound in an uncoated form and/or exhibits less diurnal variation in plasma concentration relative to prior art capsules or tablets containing the morphine compound in a sustained release form.

A method of treating pain-associated conditions in patients requiring such treatment which method includes administering to a patient an effective amount of a sustained release pharmaceutical pellet composition including a core element including at least one morphine compound having an aqueous solubility of at least 1 in and a core coating for the core element which is partially soluble at a highly acidic pH and wherein the morphine compound is available for absorption at a relatively constant rate in the intestine over an extended period of time, such that blood levels of morphine are maintained within the therapeutic range over an extended period of time.

26. A method according to claim 25 wherein the pain associated conditions relate to the treatment of acute and chronic pain.

27. A method according to claim 26 wherein the sustained release pharmaceutical pellet composition is provided in a unit dosage form and administration occurs at intervals of approximately 8 to 24 hours. DATED: 30th June, 1993 PHILLIPS ORMONDE FITZPATRICK Attorneys for: F.H. FAULDING CO. LIMITED 1 j ABSTRACT A sustained release pharmaceutical pellet composition including a core element including at least one active ingredient having an aqueous solubility of at least 1 in and a core coating for the core element which is partially soluble at highly acidic pH, and wherein the active ingredient is available for absorption at a relatively constant rate in the intestine over an extended period of time. i 4 S i t 4 II