BACKGROUND OF THE INVENTION

This invention relates to a method of making a controlled release product from an interpolymer complex and an active agent, to a controlled release product comprising an interpolymer complex having an active agent embedded therein, and to the use of an interpolymer complex as a controlled release matrix for an active agent.

The formation of physical polymer networks by interpolymer complexation is well known [see E Tsuchida & K Abe. Interactions between Macromolecules in Solution and Intermacromolecular Complexes. Springer- Veriag, New York, 1982 and E Tsuchida in J.M.S. - Pure Appl. Chem. A31(l) (1994) 1 - 15]. Interpolymer complexes have been used in medical applications such as permeable contact lenses, permeable wound dressings, cornea! implants, vascular grafts, coatings for prosthetic devices, membranes and components for artificial kidneys and blood oxygenators [MK Vogel, RA Cross &

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HJ Bixler J. Macromol. Sci. Chem. A4(3) (1970) 675-692].

As discussed by Scranton et al [Polyelectrolyte Gels. Properties. Preparations and Applications. ACS Symposium Series 480, 1992], interpolymer complexes are formed by the association of two or more complementary polymers, and may arise from electrostatic forces, hydrophobic interactions, hydrogen bonding, van der Waals forces or combinations of these interactions. Due to the long-chain structure of the polymers, once a pair of complementary repeating units associate to form a segmental complex, many other units may readily associate without a significant loss of translational degrees of freedom. Therefore the complexation process is cooperative, and stable interpolymer complexes may form even if the segmental interaction energy is relatively small. The formation of complexes may strongly affect the solubility, rheology, conductivity and turbidity of polymer solutions. Similarly, the mechanical properties, permeability and electrical conductivity of the polymeric systems may be greatly affected by complexation.

Tanaka [Polyeiectrolyte Gels. Properties. Preparation and Applications. ACS Symposium Series. 1992] classified the assemblies in biological systems into four fundamental attractive interactions, namely: Electrostatic attraction. Hydrogen bonding, Hydrophobic interaction and van der Waals interaction.

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We have shown previously [SA patent 93/4104] how two water-soluble poiymers may be converted into a water-insoluble interpolymer complex (at~neutral pH) with a specific molecular/aggregate assembly by purely mixing them in the presence of specific solvents. Unlike covalent polymer networks, interpolymer complexes are solvent reversible. Table 1 illustrates the latter in terms of aqueous solubility.

Table 1 Solubility of interpolymer complexes (Adapted from Tsuchida)

Kono et al [J. Appl. Pol. Sci. 59 (1996) 687-693] showed that the permeability of a weak polyacid-weak polybase polyelectrolyte membrane follows similar behaviour to that of solubility as shown in Table 1, i.e.. high permeability at low and high pH.

Inteφolymer complexes between chitosan and pectin or gum acacia have been applied to controlled release by Meshali et al [Int. J. Phar. 89 (1993) 177-181]. They prepared the interpolymer complexes in solution, separated the precipitate from the solution and dried it in an oven. They concluded that the physical mixture of the polymers as opposed to the inteφolymer complex, displayed the most efficient sustained release.

Inteφolymer complexes are characterized by valuable properties, namely: biological compatibility, hemocompatibility and low toxicity [AV Kharenko & VA Kemenova

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4 Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22 (1995) 232-233]. Kharenko et al prepared inteφolymer complexes from poly(methacrylic acid) and poly(ethylene glycol) and evaluated their use as a matrix for oral controlled-release formulations, particularly for theophyllme. It is stated that the inteφolymer complex is formed by hydrogen bonding of the carboxylic protons of PMA to the ether oxygens of PEG. No further description of the manufacture of the controlled release system is given.

In Japanese patent 4-312522, a method for the manufacture of a slow release tablet is given. Hydroxypropylmethylcellulose (HPMC) is suspended in hot water. Tannic acid, an acrylic acid-methylmethacrylate-dimethyl aminoethyl methacrylate polymer or a methacrylic acid-acrylic acid ester copolymer is added. The constituent which is obtained by atomization drying is compressed together with the primary medicinal compound. The slow release is achieved by the viscosity of the HPMC and by coating the tablet with a polymer. There is no mention of the formation of an inteφolymer complex or embedding of an active agent therein.

Smith et al [Ind. Eng. Chem. 51(11) (1959) 1361-1364] showed how complexation inhibitors may be utilized to re-solubilize inteφolymer complexes between poly(acrylic acid) and poly(ethylene oxide). They suggested the use of hydrogen bonding solvents amongst others for this puφose as they suggested these would compete for the hydrogen bonding sites of the respective polymers.

Injectable formulations have been prepared from inteφolymer complexes which are stabilized in solution by a complex solubilizer [WO 95/35093]. A pharmaceutical composition including a therapeutic agent and a sustained-release delivery vehicle is disclosed. The delivery vehicle comprises a solution of at least one pharmaceutically acceptable polyacid and at least one pharmaceutically water-soluble, non-ionic polymer, the polyacid and non-ionic polymer forming a stable insoluble inteφolymer complex in water at acidic pH, in an aqueous solvent including a pharmaceutically acceptable

complex solubilizer. the amount of solubilizer being effective to solubilize the insoluble inteφolymer complex. The pharmaceutical composition is intended for injection.

Dangprasiπ et al [Drug Dev. ά Ind. Pharm. 21(20) (1995) 2323-2337] disclose that diclofenac sodium controlled release solid dispersions were prepared by spray drying using ethylcellulose, rnethacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose and carbomer as single carriers and ethylcellulose - chitosan as combined carriers. Among solid dispersions of 3: 1 drug:single carrier, the system containing chitosan exhibited the slowest dissolution. Combined carriers of ethylcellulose-chitosan exhibited more dissolution retarding effect than single carrier of ethylcellulose or chitosan.

Herzfeldt et al [Pharmazemische Zeitung 128(29) (1983) 1589-1592] show that some indomethacin-poly er additive-mixtures have been spray dried by a laboratory spray dryer. The spray dried products were investigated as to their technological behaviour and their dissolution rate properties in relation to the source substance. These investigations resulted in an optimised technological behaviour by spray drying indomethacin without additives but also by spray drying in the presence of cationic polyacrylate. The rapid dissolution rate of the source substance is decreased by spray drying indomethacin in mixtures with methylcellulose and cationic polyacrylate. The spray dried products with poly vinylpyrrolidone including the addition of sodium lauryl sulphate consists of nano-and microcapsules. There is no mention of the formation of inteφolymer complexes.

A need exists for novel controlled release products for oral administration, where the release of the active agent from the product can be controlled over a range of release rate and profiles and at different pHs, made by methods which differ from the existing methods described above, which methods provide various advantages such as cost reduction and enhancement of up-scaleability of the methods.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided a method of making a solid inteφolymer complex which may be used as a controlled release matrix for a controlled release product for oral administration, from a first polymer and one or more second complementary polymers capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, which method includes the steps of:

(1) dissolving the first polymer in a solvent therefor;

(2) dissolving the second complementary polymer in a solvent therefor:

(3) if necessary, adding a complexation inhibitor to the solution of step (1) or the solution of step (2);

(4) mixing together the solutions of steps (1) and (2);

(5) if necessary, adjusting the pH of the mixture of step (4); and

(6) spraying the product of step (5) into a vessel to remove at least partially the solvents and thereby to produce solid particles of the inteφolymer complex.

According to a second aspect of the invention there is provided a solid inteφolymer complex for use as a controlled release matrix for a controlled release product for oral administration, which inteφolymer complex is made from a first polymer and one or more second complementary polymers capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, by a method which includes the steps of:

(1) dissolving the first polymer in a solvent therefor;

(2) dissolving the second complementary polymer in a solvent therefor:

(3) if necessary, adding a complexation inhibitor to the solution of step (1) or the solution of step (2);

(4) mixing together the solutions of steps (1) and (2);

(5) if necessary, adjusting the pH of the mixture of step (4); and

(6) spraying the product of step (5) into a vessel to remove at least paπially the solvents and thereby to produce solid panicles of the inteφolymer complex.

According to a third aspect of the invention there is provided a process of makine a controlled release product for oral administration from a inteφolymer complex and an active agent, wherein the inteφolymer complex is made from a first polymer and a second complementary polymer capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, which includes the steps of:

(a) dissolving the first polymer in a solvent therefor;

(b) dissolving the second complementary polymer in a solvent therefor;

(c) if necessary, adding a complexation inhibitor to the solution of step (a) or the solution of step (b);

(d) mixing together the solutions of steps (a) and (b);

(e) if necessary, adjusting the pH of the mixture of step (d);

(0 spraying the product of step (e) into a vessel to remove at least paπially the solvents and thereby to produce solid panicles of the inteφolymer complex; and

(g) incoφorating the active agent into the inteφolymer complex to form the controlled release product.

The process may be carried out in various ways.

Firstly, the process may be carried out by:

(a) dissolving the first polymer in a solvent therefor;

(b) dissolving the second complementary polymer in a solvent therefor;

(c) if necessary, adding a complexation inhibitor to the solution of step (a) or the solution of step (b): (g) providing the active agent in the form of a dry powder or in the form of a solution, dispersion, suspension, emulsion or slurry of the active agent in a liquid medium; and either (d)(i) mixing the product of step (g) with either the solution of step (a) or the solution of step (b) and then mixing together the solutions of step (a) and step (b); or (d)(ii) mixing together the solutions of step (a) and step (b) and the product of step

(g);

(e) if necessary, adjusting the pH of the mixture of step (d); and then

(f) spraying the product of step (e) into a vessel to remove at least paπially the solvents and the liquid medium when present and thereby to produce solid panicles of the inteφolymer complex with the active agent embedded or encapsulated therein.

Secondly, the process may be carried out by preparing the inteφolymer complex as set out above in steps (a) to (f) and then:

(g) mixing the active agent in solid or liquid form with the inteφolymer complex, and compressing the product to produce a tablet or a mini tablet.

Thirdly, the process may be carried out by performing steps (a) to (e) above and then: (f) spraying the product of step (e) into a vessel in which the active agent is being fluidized thereby encapsulating the active agent panicles in a coating of the inteφolymer complex.

According to a fourth aspect of the invention there is provided a controlled release

product for oral administration which comprises a solid inteφolymer complex and an active agent incoφorated into the inteφolymer complex, wherein the in _t eφolymer complex is made from a first polymer and a second complementary polymer capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, by a method which comprises the steps of:

(1) dissolving the first polymer in a solvent therefor;

(2) dissolving the second complementary polymer in a solvent therefor:

(3) if necessary, adding a complexation inhibitor to the solution of step (1) or the solution of step (2);

(4) mixing together the solutions of steps (1) and (2);

(5) if necessary, adjusting the pH of the mixture of step (4); and

(6) spraying the product of step (5) into a vessel to remove at least paπially the solvents and thereby to produce solid panicles of the inteφolymer complex.

According to a fifth aspect of the invention there is provided the use of a solid inteφolymer complex formed from a first polymer and a second complementary polymer capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, by a method which comprises the steps of:

(1) dissolving the first polymer in a solvent therefor;

(2) dissolving the second complementary polymer in a solvent therefor;

(3) if necessary, adding a complexation inhibitor to the solution of step (1) or the solution of step (2);

(4) mixing together the solutions of steps (1) and (2);

(5) if necessary, adjusting the pH of the mixture of step (4); and

(6) spraying the product of step (5) into a vessel to remove at least paπially the solvents and thereby to produce solid panicles of the inteφolymer complex; as a controlled release matrix for a controlled release product for oral administration.

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10

The inteφolymer complex may be formed from a first polymer and one or more second complementary polymers, such that the first polymer and the one or more second complementary polymers all interact to form the inteφolymer complex.

The solvents used in steps (1) and (2) of the method of the invention, the solvents used in steps (a) and (b) of the process of the invention and the liquid medium used in step (g) of the process of the invention, may consist of single solvents or may be a mixture of solvents or a single liquid medium or may be a mixture of liquid media. Further, the solvents used in steps (1) and (2) and in steps (a) and (b) may be the same or different. The liquid medium of step (g) may be a solvent for one or more of the first or second complementary polymers.

The spraying in step (6) or step (f) may be achieved by spray drying or by spray granulation techniques or the like. Preferably the spraying is spray drying.

A complexation inhibitor must be present to prevent the inteφolymer complex from precipitating from solution prior to step (6) or step (f). The solvent or solvents or liquid medium used may be chosen to act as complexation inhibitors. Alternatively, where none of the solvent or solvents or liquid medium is a complexation inhibitor then a complexation inhibitor such as for example acetic acid, ethanol, acetone. DMSO or a hydrogen bonding substance or the like, must be added to the solvent or solvents in steps (1) or (2) or in steps (a) or (b) and optionally also to the liquid medium.

The complexation inhibitors are preferably volatile complexation inhibitors, viz. hydrogen bonding solvents such as ethanol. acetone or the like with relatively low boiling points.

DEFINITIONS

The active agent may be a drug for humans or animals, or a food supplement such as a vitamin or a mineral, or the like.

The term polymer may refer to the first polymer or to any one of the second complementary polymers.

The term polymer includes copolymers.

By complexation there is meant reversible physical molecular forces such as hydrogen bonding, hydrophobic interactions, van der Waals forces, electrostatic-, ionic- or Coulomb forces and combinations of these interactions and excludes irreversible chemical forces such as covalent bonding.

The pH of the polymer solution before spray drying determines the inteφolymer complex formed and the release rate of active agent from the dosage form and this must be adjusted, if necessary, to give the desired product. For hydrogen bonding inteφolymer complexes in which one of the polymers is a polyacid. the preferred pH of the solution prior to spray drying is preferably below the pKa value of the acid groups on the polyacid.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 to 22 are dissolution graphs of the products of Examples 1 to 22; Figure 23 shows the in vivo results of Examples 4, 7 and 8; and. Figure 24 is the in vivo result of the product of Example 11.

DESCRIPTION OF EMBODIMENTS

According to a first aspect of the invention there is provided a method of making a solid inteφolymer complex which may be used as a controlled release matrix for a controlled release product for oral administration, from a first polymer and one or more second complementary polymers capable of complexing with the first polymer to form the inteφolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, which method includes the steps of:

(1) dissolving the first polymer in a solvent therefor;

(2) dissolving the second complementary polymer in a solvent therefor;

(3) if necessary, adding a complexation inhibitor to the solution of step (1) or the solution of step (2);

(4) mixing together the solutions of steps (1) and (2);

(5) if necessary, adjusting the pH of the mixture of step (4); and

(6) spraying the product of step (5) into a vessel to remove at least paπially the solvents and thereby to produce solid panicles of the inteφolymer complex.

This method is the crux of the present invention.

The inteφolymer complex made by the method of the invention is intended for use as a controlled release matrix for a controlled release product for oral administration. In this regard, an active agent is incoφorated into the inteφolymer complex to form the controlled release product.

The incoφoration of the active agent into the inteφolymer complex may be achieved in various ways including incoφorating the active agent into the inteφolymer complex as it is formed, so that the active agent is embedded or encapsulated in the inteφolymer complex, by coating the active agent panicles with the inteφolymer complex in a fluidized bed, or by post mixing the inteφolymer complex with the active agent and then compressing the result to form a tablet of the inteφolymer complex with the active

agent incoφorated therein.

The controlled release products of the invention may be designed to have a wide range of release rates and profiles, including a substantially zero-order release rate over a period of time between 2 and 72 hours. In addition, the controlled release products of the invention may be either pH insensitive, acid sensitive or base sensitive. pH insensitive products release the active agent at the same rate inespective of the pH of the suπounding environment; acid sensitive products release the active agent faster in an acidic environment: and, base sensitive products release the active agent faster in a basic environment.

As stated above, the active agent may be a drug for humans or animals, in which case the controlled release product of the invention will be a controlled release pharmaceutical product or a controlled release veterinary product. Alternatively, the active agent may be a food supplement such as a vitamin or a mineral.

Suitable classes of drugs for use in the controlled release product of the invention include: opioid agonists, opioid antagonists, benzodiazepines,, butyrophenones. GABA stimulators, substituted phenols, antiarrhythmics, beta blockers, ACE inhibitors, calcium channel blockers, anthihypeπensives, antihypeπensive/angina drugs, diuretics, angina-acting drugs, antihypeπensive/angina/ vasodilator-acting drugs, hypotensive- acting drugs, antiemetics, antifungals, anti-parkinson drugs, bronchodilators, antimigraine drugs, oxytocic drugs, antidiuretics, antihyoperglycemics, macromolecular drugs, amino acids, polysaccharides, polypeptides, antigens, nucleosides, antibodies, vitamins, enzymes, central nervous system-acting drugs, cardiovascular-acting drugs, renal vascular-acting drugs, anxiolytics, analgesics, anesthetics, antianginals and antibiotics.

Specific examples of suitable drugs are: nicotine, atropine, scopolamine, ondansetron, sumatriptan. rizatriptan. naratriptan, ketorolac tromethamine, oxybutinin, meclofenamate. piroxicam, ketoprofen. indomethacin. ibuprofen, diclofenac, flurbiprofen, lornoxicam, meioxicam, celecoxib, montelukast. cyclosporin, nimesulide, zidovudine. etoposide. tromadol, moφhine, diltiazem. cisapride, omeprazole. fentanyl, alfentanil, sufentanil. lofentanil. carfentanil, naloxone. nalbuphene, diazepam, lorazepam, lormetazepam. midazolam. oxazepam, triazolam. ketamine, levodopa. bretylium, captopril. ramipril, clonidine, dopamine, enalapril, esmolel. furosemide. isosorbide. labetolol, lidocaine, metolazone, metoprolol, nadolol, nifedipine, nicardipine, nitrendipine. nisoldipine. amlodipine, nitroglycerin, nitroprusside, propranolol, benzquinamide, meclizine, cyclizine, metoclopramide, prochloφerazine, trimethobeπzamide. clotrimazole. nystatin. carbidopa, verapamil, levodopa. albuterol, aminophylline, beclomethasone, dyphylline, epinephrine, flunisolide, isoproterenol HCl, metaproterenol, oxtriphylline, terbutaline, theophyllme, ergotamine, dihydroergotamine, methysergide, propranolol, atenolol, suloctidil, salmeterol and pentoxiphylline.

Drugs of particular interest are verapamil, diltiazem. indomethacin, diclofenac, isosorbide-5-mononitrate, zidovudine, pentoxiphylline, levodopa/carbidopa and cisapride.

The polymers used to form the inteφolymer complex of the invention may be linear, branched, star shaped, comb shaped or cross-linked. Preferably the polymers are linear or combinations of linear and cross-linked hydrophilic polymers or their co-polymers.

At least one of the polymers forming the inteφolymer complex must be a synthetic polymer. Synthetic polymers offer the advantages, over naturally occurring polymers, of homogeneity and predictability of properties and chemical composition.

When the inteφolymer complex is a hydrogen bonding complex and the first polymer is a polyacid, preferably the pH is such that the polyacid is in its unionized state with no charge, i.e. , pH <pKa value of the acid groups, and the second complementary polymer is a polymer with hydrogen bonding sites.

When the inteφolymer complex is a polyelectrolyte complex, preferably the first polymer is a strong polyacid and the second complementary polymer is a weak polybase.

Examples of suitable polymers from which the first polymer and the second complementary polymer may be selected are: alginates; alkyl and hydroxyalkylcelluloses; carboxymethylcellulose and its salts; carrageenan; cellulose and its derivatives; guar gum; gum arabic: methyl vinyl ether/maleic anhydride copolymers; pectins; poly (aery lamide); poly (aery lie acid) and its salts; poly (ethylene glycol); poly (ethylene imine); poly (ethylene oxide); poly(me_hacrylic acid); poly (vinyl acetate); poly(vinyl alcohol); poly(vinyl amine); poly(vinyl) pyπolidone); poly(vinyl sulphonic acid); starches and their derivatives; styrene/maleic anhydride copolymers: xanthan gum; or the like and their copolymers.

For diclofenac or its sodium salt, the preferred inteφolymer complex may be formed from: methyl methacrylate/methacrylic acid copolymer with vinyl pynolidone/vinyl acetate copolymer and with hydroxypropy -methylcellulose, in a preferred mass ratio of 1:1:1, with the mass ratio of drug to inteφolymer complex being preferably 1: 1; or methylmethacrylate/methacrylic acid copolymer with hydroxypropylmethylcellulose, in a preferred mass ratio of 10:90, with the mass ratio of drug to inteφolymer complex being preferably 1:1.

These systems are illustrated in Examples TP 315, TP 317 and TP 343.

For verapamil, the prefened inteφolymer complex may be formed from: methyl methacrylate/methacrylic acid copolymer with hydroxypropylmethylcellulose. in a preferred mass ratio of 10:90, with the mass ratio of drug to inteφolymer complex being preferably between 6:4 to 4:6.

These systems are illustrated in Examples TP 283 and TP 310.

The solvents and liquid medium used may be the same or different. Further, each of the first polymer, the second complementary polymer or polymers is dissolved in a mixture of solvents and/or liquid media. The active agent may be dissolved, dispersed, suspended, emulsified or slurried separately in the solvents or liquid medium or may be dissolved, dispersed, suspended, emulsified or slurried together with the polymers in a mixture of solvents and/or liquid media.

Suitable solvents and liquid media include: water; ethanol, propanol and other alcohols; acetone and the like and mixtures thereof.

The solvent or solvents or liquid medium may be chosen to act as complexation inhibitors, to prevent the inteφolymer complex from precipitating prior to step (4) or step (d). Alternatively, a complexation inhibitor such as acetic acid or acetone must be added to the solvent or solvents or liquid medium. Generally, hydrogen bonding solvents such as acetone and ethanol are used as complexation inhibitors. Another example of a non volatile complexation inhibitor is glycerine.

The spraying in step (6) or step (f) may be achieved by spray drying, spray coating or spray granulation techniques. Preferably the spraying is spray drying.

The spray drying, spray coating or spray granulation may be carried out using conventional techniques.

For example, suitable parameters for spray drying are as follows: Inlet temperature - between 60°C and 180°C, preferably between 120°C and 140°C; peristaltic pump speed range - between 60 ml/h and 800 ml/h, resulting in an outlet temperature of between 70°C and 110°C, preferably between 180 ml/h and 600 ml/h, resulting in an outlet temperature of between 85 °C and 95 °C; air flow rate - between 200 and 800 Nl/h, preferably between 500 and 600 Nl/h; total concentration of polymer in solution - between 0.1 and 10%, preferably with a solid content between 2 and 5 % .

The solid product of step (6) or step (f) may be blended with conventional pharmaceutical excipients such as a glidant (eg silicic acid), a lubricant (eg magnesium stearate), and a disintegrant (eg sodium starch glycolate), according to conventional techniques and in conventionsl quantities.

In step (g), compression includes conventional compression in a tableting machine as well as extrusion and other techniques where pressure is applied to the mixture of inteφolymer complex and active agent.

The result of step (g) above may be a conventional tablet or a mini tablet for incoφoration for example into a capsule.

The controlled release product produced by the method of the invention may be used as such or may be pressed into tablets or used in other dosage forms such as capsules. Preferably the controlled release product is pressed into tablets. When the controlled release product of the method of the invention is pressed into tablets, the product may be mixed with suitable amounts of conventional excipients such as disintegrants, e.g., crosslinked poly(vinyl pynolidone), microcrystalline cellulose and sodium starch glycolate. and lubricants, e.g., calcium stearate and magnesium stearate.

The invention will now be described in more detail with reference to the following examples and the figures. All the Examples were earned out using a Mini Spray Dryer 190 from Bϋchi Laboratorium-Technik.

EXAMPLES

Example 1 (TP50)

The following solutions were prepared: (a) lOOg of a 2% solution of poly(vinyI alcohol) in water, (b) lOOg of a 2% solution of poly(ethylene oxide) in a water: ethanol (1: 1) mixture. 4g Indomethacin was added to solution (b), the resulting suspension was mixed with solution (a) and spray dried. The spray dried granules were blended with a lubricant and compressed into a tablet and in vitro dissolution studies were performed as illustrated in Figure 1.

Example 2 (TP70)

Method as in Example 1 with (a) lOOg of a 2% solution of poly (aery lie acid) in a wateπethanol (1:1) mixture, (b) lOOg of a 2% solution of hydroxyethyl cellulose in water. 4g Diltiazem hydrochloride was dissolved in the polymer solution mixture. In vitro dissolution studies were preformed as illustrated in Figure 2.

Example 3 (TP120)

Method as in Example 1 with (a) 20g of a 10% solution of vinyl pyrrolidone/vinyl acetate copolymer in water, (b) lOOg of a 2% solution of poly(acrylic acid) in water, (c) lOOg of a 2% solution of gum arabic in water. 6g verapamil hydrochloride was dissolved in 150ml ethanol (ethanol acts as the volatile complexation inhibitor). To this solution was added (a), then (b) and then (c). In vitro dissolution studies were preformed as illustrated in Figure 3.

Example 4 (TP121 and TP142)

Method as in Example 1 with (a) 1 300g of a 2 % solution of vinyl methyl ether/maleic anhydride copolymer in water, (b) 1 300g of a 2 % solution of vinyl pyrrolidone/vinyl acetate copolymer in water and, (c) 1 300g of a 2 % solution of gum arabic in water. 78g verapamil was added to the premixed polymer solution followed by the addition of 1 / acetone and 1 / ethanol, the latter two solvents act as the volatile complexation inhibitor. In vitro dissolution studies were preformed as illustrated in Figure 4. In vivo results are shown in Figure 23, after single dose administration to human volunteers (n=6).

Spray-drying parameters

Inlet Temperature: 139 - 140°C

Outlet Temperature: 88 - 89° C

Air flow: 600 Nl/h

Peristaltic Pump Speed. ¹ 540ml/h

Example 5 (TP123)

Method as in Example 1 with (a) 20g of a 10% solution of vinyl pyrrolidone/vinyl acetate copolymer in water, (b) lOOg of a 2% solution of poly(acrylic acid), and (c) lOOg of a 2% solution of gum arabic in water. 6g verapamil was dissolved in 100ml ethanol. To this was added (a) and (c). Then 100ml acetone was added as a volatile complexation inhibitor. To this mixture was added (b). In vitro dissolution studies were performed as illustrated in Figure 5.

Example 6 (TP240)

Method as in Example 1 with (a) 49g of a 10% solution of vinyl methyl ether/maleic acid copolymer in water, (b) 21g of a 10% solution of vinyl pynolidone/vinyl acetate copolymer in water. 7g verapamil was dissolved in a mixture of 150ml water and 100ml acetone, the latter as a volatile complexation inhibitor. To this was added (a)

and then (b). In vitro dissolution studies were preformed as illustrated in Figure 6.

Example 7 (TP267)

Method as in Example 1 with (a) 140g of a 5 % solution of sodium alginate in water,

(b) 140g of a 5 % solution of vinyl pynolidone/vinyl acetate copolymer in water and,

(c) 140g of a 5 % solution of hydroxypropyl methylcellulose in water. 21g verapamil was dissolved in 400ml water and added to the premixed polymer solution followed by the addition of 300ml acetone. In vitro dissolution studies were preformed as illustrated in Figure 7. In vivo results are shown in Figure 23.

Spray-drying parameters

Example 8 (TP283)

Method as in Example 1 with (a) 25g of a 10 % solution of poly(methacrylic acid-co- methylmethacrylate) in n-propanol and. (b) 225g of a 10 % solution of hydroxypropyl methycellulose in water. 37.5g verapamil was dissolved in a mixture of solution (b) and 300ml acetone followed by the addition of solution (a) to the mixture. In vitro dissolution studies were preformed as illustrated in Figure 14. In vivo results are shown in Figure 23.

Spray-drying parameters

Inlet Temperature: 140°C

Outlet Temperature: 90 - 96°C

Air flow: 500 - 600 Nl/h

Peristaltic Pump speed: 420 ml/h

Example 9 (TP162)

Method as in Example 1 with (a) 15g of a 10% solution of poly(acrylic acid) in water, (b) 15g of a 10% solution of vinyl pyrrolidone/vinyl acetate copolymer in water and (c) 15g of a 10% solution of hydroxypropylcellulose in water. 4g diclofenac was dissolved in a mixture of acetone and ethanol (150ml of each) and 100ml water was added to the system before spray drying. In vitro dissolution studies were performed as illustrated in Figure 9.

Example 10 (TP316)

Method as in Example 1 with (a) 1.5g of a 10% solution of methyl methacrylate/ methacrylic acid copolymer in a 40:60 mixture of wateπacetone, (b) 19.5g of a 10% solution of vinyl pyrrolidone/vinyl acetate copolymer in water, and (c) 9g of a 10% solution of hydroxypropylmethyl cellulose in water. 3g Diclofenac was dissolved in 50ml acetone, the acetone acts as a volatile complexation inhibitor. To this was added (a), then (b) and then (c). In vitro dissolution studies were performed as illustrated in Figure 10.

Example 11 (TP282)

Method as in Example 1 with (a) 200g of a 2.5 % solution of sodium alginate in water, (b) lOOg of a 5 % solution of vinyl pyrrolidone/vinyl acetate in water and, (c) lOOg of a 5 % solution of hydroxypropyl methylcellulose in water. 15g diclofenac was dissolved in 300ml acetone and added to the premixed polymer solution. In vitro dissolution studies were performed as illustrated in Figure 11. In vivo results are shown in Figure 24, after single dose administration to human volunteers.

Spray-drying parameters

Inlet Temperature: 140°C

Outlet Temperature: 90°C

Air flow: 600 Nl/h

Peristaltic Pump speed: 240 ml/h

Example 12 (TP21 and TP22)

Method as in Example 1 with (a) lOOg of a 1 % solution of poly (vinyl pyrrolidone) in water, (b) lOOg of a 1 % solution of poly(ethylene oxide) in water and, (c) lOOg of a 1 % solution of poly(acrylic acid) in water. Pre-mix: 3g verapamil was dissolved in solution (c), admixed with solution (a) and (b), 150ml acetone was added as a complexation inhibitor and the mixture was spray dried. Post-mix: solution (a), (b) and (c) were mixed, 150ml acetone was added as a complexation inhibitor and the mixture was spray dried. Then 3g verapamil was post mixed with the inteφoiymer complex powder. In vitro dissolution studies were performed as illustrated in Figure 12. Notice the difference in the release profiles.

Example 13 (TP13)

Method as in Example 1 with (a) 60g of a 2% solution of methyl vinyl ether/maleic anhydride copolymer in water and, (b) 140g of a 2% solution of vinyl pyrrolidone/vinyl acetate copolymer in ethanol. 4g verapamil was dissolved in solution (b), admixed with solution (a) and the mixture was spray dried. In vitro dissolution studies were performed as illustrated in Figure 13.

Example 14 (TP40)

Method as in Example 1 with (a) lOOg of a 2% solution of methyl vinyl ether/maleic anhydride copolymer in water and, (b) lOOg of a 2% solution of vinyl pynolidone/vinyl acetate copolymer in ethanol. 4g verapamil is dissolved in solution (b), admixed with solution (a) and the mixture was spray dried. In vitro dissolution studies were performed as illustrated in Figure 14.

Example 15 (TP43)

Method as in Example 1 with (a) lOOg of a 2% solution of poly(acrylic acid) in a water: ethanol (1: 1) mixture and. (b) lOOg of a 2% solution of hydroxyethylcellulose in water. 4g verapamil is dissolved in solution (a), admixed with solution (b) and the mixmre was spray dried. In vitro dissolution smdies were performed as illustrated in Figure 15.

Example 16 (TP45)

The following solutions were prepared: (a) lOOg of a 2% solution of methyl vinyl ether/maleic anhydride copolymer in water, (b) lOOg of a 2% solution of gum arabic in water, (c) lOOg of a 2% solution of vinyl pyπolidone/vinyl acetate copolymer (60:40) in ethanol and, (d) a solution of 6g verapamil in ethanol. The solutions (a) (b) and (c) were admixed, mixed with the solution (d) and spray dried. The spray dried granules were compressed into a tablet and in vitro dissolution studies were performed in acid (0.1M HCl) and base (phosphate buffer pH 7.5) as illustrated in Figure 16.

Example 17 (TP49)

Method as in Example 1 with (a) lOOg of a 2 % solution of methyl vinyl ether/maleic anhydride copolymer in water and, (b) lOOg of a 2% solution of hydroxypropylcellulose in water. 4g indomethacin was slurried in 50ml ethanol, mixed with solutions (a) and (b) and the mixmre was spray dried. In vitro dissolution smdies were performed as illustrated in Figure 17.

Example 18 (TP60)

Method as in Example 14 with sodium diclofenac in place of verapamil. In vitro dissolution smdies were performed as illustrated in Figure 18.

Example 19 (TP66)

Method as in Example 1 with (a) 97% of a 2% solution of methyl vinyl ether/maleic

anhydride copolymer in water and, (b) 97g of a 2% solution of sodium carboxymethylcellulose in water. 3.88g sodium diclofenac was dissolved in 50ml ethanol and admixed with solutions (a) and (b) and the mixmre was spray dried. In vitro dissolution smdies were performed as illustrated in Figure 19.

Example 20 (TP73)

Method as in Example 1 with (a) lOOg of a 2% solution of poly(vinyl alcohol) in water and, (b) lOOg of a 2% solution of poly(ethylene oxide) in water: ethanol (1:1). 4g diltiazem was dissolved in the mixmre of solutions (a) and (b) and the mixmre was spray dried. In vitro dissolution smdies were performed as illustrated in Figure 20.

Example 21 (TP76)

Method as in Example 1 with (a) 64g of a 2% solution of poly(acrylic acid) in water: ethanol (1:1), (b) 64g of a 2% solution of poly(ethylene oxide) in water and, (c) 64g of a 2% solution of hydroxyethylcellulose in water. 3.84g diltiazem was dissolved in a mixmre of solutions (b) and (c), admixed with solution (a) and the mixmre was spray dried. In this example ethanol acts as the complexation inhibitor. In vitro dissolution smdies were performed as illustrated in Figure 21.

Example 22 (TP343)

Method as in Example 1 with (a) lOg of a 10% dispersion of methyl methacrylate/methacrylic acid copolymer, (b) lOg of a 10% solution of vinyl pyrrolidone/vinyl acetate copolymer in water and, (c) lOg of a 10% solution of hydroxypropylmethylcellulose in water. 3.09g diclofenac was preprotonated, filtered and washed with distilled water before redissolving it in 50ml acetone. The drug solution was added to (a) which became a clear solution, then admixed with (b) and (c) and spray dried. In this example acetone acts as the complexation inhibitor. In vitro dissolution smdies are performed as illustrated in Figure 22.

Tsible 2 Experimental interpolymer complexation systems (All the systems contain 1.5% magnesium stearate as a die lubricating agent. All the tablets are compressed to 45 cam except if indicated otherwise.) Tablet size 10 mm unless specified.

System Pnig (drug:polymer Polymer Composition Additional parameters reference ratio excluding Mg stearate)

TP6 Verapamil (1 :5.25) PVME/MA S-97 : PVP/VAc E-635 (1: 1)

(a) lOOg of 5 % vinyl methyl elher/maleic acid copolymer in water

(b) lOOg of 5% vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ethanol to TP7 Verapamil (1 : 1) PVME/MA S-97 : PVP VAc E-635 (1 : 1)

C (a) 100 g of 2 % vinyl methyl ether/maleic acid copolymer in water 00 (I)) 100 g of 2 % vinyl pyrrolidune/vinyl acetate copolymer (60:40) in ethanol

TP8 Verapamil (1 : 1) PVME/MA S-97 : PVP VAc E-535 (30:70)

(a) 60g of 2% vinyl methyl ether/maleic acid copolymer in water

(b) 140g of 2% vinyl pyrrolidone/vinyl acetate copolymer in (50:50) t ethanol

TPIO Verapamil (1 : 1) PVME/MA S-97 : PVP/VAc E-535 (5:95)

(a) lOg of 2% vinyl methyl elher/maleic acid copolymer in water

(b) 190g of 2% vinyl pyrrolidone/vinyl acetate copolymer in (50:50) ethanol TPI I Verapamil (1:5.25) PVME/MA S-97 : PVP/VAc E-635 (1:1) 10% microcrystalline cellulose post mixed

M (a) lOOg of 5 % vinyl methyl ether/maleic acid copolymer in water

(b) lOOg of 5 % vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ethanol

(c) 10 % niicrocrysfalline cellulose postmixed

TPI2 Verapamil (1 : 1) PVME/MA S-97 : PVP/VAc E-535 (30:70) 10% starch post mixed

(a) 60g of 2% vinyl methyl ether/maleic acid copolymer in water

(b) 1 0g of 2% vinyl pyrrolidone/vinyl acetate copolymer (50:50) in ethanol

(c) 10 % starch postmixed

TP13 Verapamil (1 : 1) PVME/MA S-97 : PVP/VAc E-335 (30:70)

TPI4 Verapamil (1:1) PVMEMA S-97 : PVPVAc E-335 (30:70) 10% crospovidone post mixed

(a) 60g of 2 % vinyl methyl ether/maleic acid co|x>lyιιter in water

(b) I 0g of 2% vinyl pyrrolidone/vinyl acetate copolymer (30:70) in ethanol

(c) 10% of crospovidone postmixed

TPI5 Verapamil (1:1) PVP K90 : PAA K752 (90:10)

(a) I80g of 2% poly(vinyl pyrrolidone) in water

(b) 20g υf 2% |oly(acrylic acid) in water

TP16 Verapamil (1:1) PVME/MA S-97 : PVP/VAc E-535 (20:80)

(a) 40g of 2 % vinyl methyl ether/maleic acid copolymer in water

(b) 160g of 2% vinyl pyrrolidone/vinyl acetate copolymer (30:70) in ellianol

TPI7 Verapamil (1:1) PVME/MA S-97 : PVP/VAc E-335 (40:60)

(a) 80g of 2% vinyl methyl elher/maleic acid copolymer in water

(b) I20g of 2% vinyl pyrrolidone/vinyl acetate copolymer (30:70) in ellianol

ITPI8 Verapamil (1:1) PVMEMA S-97 : PVP/VAc E-535 (1:1)

(a) lOOg of 2% vinyl methyl elher/maleic acid copolymer in water

(b) lOOg of 2 % vinyl pyrrolidone/vinyl acetate copolymer (50:50) in ellianol

TPI9 Verapamil (1:1) PVME/MA S-97 : PVP/VAc E-335 (20:80) m (a) 40g of 2% vinyl methyl elher/maleic acid copolymer in water

(b) I60g of 2% vinyl pyrrolidone/vinyl acetate copolymer (30:70) in o. ellianol

ITP20 Verapamil (1:1) PVP K90 : PAA 752 (20:80)

(a) 160g of 2% poly( vinyl pyrrolidone) in water

(b) 40g of 2% ₍ >oly(acrylic acid) in water

TP2I Verapamil (1:1) PVP K90 : PEO N10 : PAA 752 (1:1:1) Post mixed

TP22 Verapamil (1:1) PVP K90 : PEO NIO : PAA 752 (1:1:1) SameasTP2l

TP23 Verapamil (1:1) PVME/MA S-97 : PVP/VAc E-535 (40:60)

(a) 80g of 2 % vinyl methyl ether/maleic acid copolymer in water

(b) 120g of 2% vinyl pyrrolidone/vinyl acetate copolymer (50:50) in ethanol

TP24 Verapamil (1: 1) PVME/MA S-97 : PVP/VAc E-635 (20:80)

(a) 40g of 2% vinyl methyl elher/maleic acid co|x>lymer in water

(b) I60g of 2% vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ethanol

TP25 Verapamil (1 : 1) PVME MA S-97 : PVP/VAc E-635 (30:70)

(a) 60g of 2% vinyl methyl ether/maleic acid copolymer in water

(I)) I40g of 2% vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ellianol

TP27 Verapamil (1 : 1) PVP K90 : PAA K752 (50:50)

(a) lOOg of 2 % |κ>ly(vinyl pyrrolidone) in water

(b) lOOg of 2 % poly (aery lie acid) in water

TP28 Verapamil (1 : 1) PVME/MA S-97 : PVP/VAc E-535 (15:85)

(a) 170g of 2 % vinyl pyrrolidone/vinyl acetate copolymer (50:50) in water (l>) 30g of 2 % vinyl methyl elher/maleic acid copolymer in water

TP29 Verapamil (1 : 1) PVME/MA S-97 : PVP/VAc E-535 (15:85) Post mixed

(a) 170g of 2 % vinyl pyrrolidone/vinyl acetate copolymer (50:50) in ellianol

(b) 30g of 2 % vinyl methyl ether/maleic acid co|x>lymer in water

(c) drug post mixed

TP30 Verapamil (1 : 1) PVME MA S-97 : PVP/VAc E-635 (40:60)

(a) 80g of 2% vinyl methyl ether/maleic acid copolymer in water

(b) 120g of 2% vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ellianol

TP32 Verapamil (1 : 1) PVME MA S-97 : PVP/VAc E-535 (50:50)

(a) lOOg of 2% vinyl methyl ether/maleic acid copolymer in water

(b) lOOg of 2% vinyl pyrrolidone/vinyl acetate copolymer (30:70) in ethanol

TP33 Verapamil (1 : 1) PVME MA S-97 : PVP/VAc E-535 (20:80)

(a) I60g of 2% vinyl pyrrolidone/vinyl acetate cojxolymer (50:50) in ethanol

(b) 40g of 2% vinyl methyl elher/maleic acid copolymer in water

to

C CD 1/1

H rπ in X m

73

C r m- σ.

TP67 Sodium Diclofenac (1:1) PVP K90 : PEO NIO : PAA K752 (1:1:1)

(a) 80g of 2 % poly(acιylic acid) in water

(b) 80g of 2 % |ioly(ethylene oxide) in water

(c) 80g of 2 % ρoly(vinyl pyrrolidone) in water

TP68 Sodium Diclofenac (1:1) PVME/MA S-97 : HPC 99LF (1:1)

(a) lOOg of 2 % vinyl methyl ether/maleic acid copolymer in water

(b) lOOg of 2 % hydroxypropyl cellulose in water

TP69 Sodium Diclofenac (1:1) PAA K752 : HEC 250HX : PEO NIO (1:1:1)

(a) 71g of 2 % polyethylene oxide) in water

(b) 7lg of 2 % hydroxyethyl cellulose in water

(c) 71g of 2 % poly(acrylic acid) in water

TP70 Diltiazem (1:1) PAAK752: HOC 250IIX (1:1)

(a) lOOg of 2 % poly(acrylic acid) in water

(I)) lOOg of 2 % hydroxyethyl cellulose in water

TP73 Diltiazem (1:1) PVA 107: PEO NIO (1:1)

TP74 ^• Diltiazem (1:1) PVME/MA S-97 : PVP/VAc E-635 (1:1)

(a) lOOg of 2 % vinyl methyl ether/maleic acid copolymer in water

(b) lOOg of 2 % vinyl pyrrolidone/vinyl acetate copolymer (60:40) in ethanol

TP75 Diltiazem (1:1) PVME/MA S-97 : HPC 99LF (1:1)

(a) lOOg of 2 % hydroxypropyl cellulose in water

(b) lOOg of 2 % vinyl methyl ether/maleic acid copolymer in water

TP76 Diltiazem (1:1) PAA K752 : PEO NIO : HEC 250HX (1:1:1)

TP77 Diltiazem (1:1) PVME/MA S-97 : PVP/VAc E-635 : Gum Arabic (1:1:1)

(a) 70g of 2 % vinyl methyl ether/maleic acid copolymer in water

(b) 70g of 2 % vinyl pyrrolidone/vinyl acetate copolymer (60:40) in water

(c) 70g of 2 % gum arabic in water

TP78 Diltiazem (1:1) PAA K752 : PVP/VAc E-635 : HEC 250HX (1:1:1)

(a) 70g of 2 % poly(acrylic acid) in water

(b) 70g of 2 % hydroxyethyl cellulose in water

(c) 70g of vinyl pyrrolidone/vinyl acetate copolymer (60:40) in water/ethanol (1:1)

11

C 00 v.

rn t/i X

M σ

t

C 00

rn

to

C

00 l/l

H

KJ a.

1/1

C 00

to

00 1/1

m

M en

to

C 00

m in X m

KJ

to C 00 ii

rn in

W σ

Key:

HEC I lydroxyelhylcelliilose

HPC I lydroxypropy (cellulose

HPMC Ilydroxypropylmethylcellulose

PAA Poly(acrylic acid)

PEO Poly(etlιylene oxide)

PMMA/MA Methyl niethaciylate/Methacrylic acid copolymer

PVA Poly(viιιyl alcohol)

PVAc Poly(vinyl acetate)

PVME/MA Vinyl methyl elher/Maleic acid copolymer m PVP Poly (vinyl pyrrolidone)

PVP/VAc Vinyl pyrrolidone/vinyl acetate copolymer