Hydrophilic/lipophilic polymeric matrix dosage formulation

Description of the invention

The invention relates to a controlled release multilayer tablet containing ropinirole and the use of ropinirole to prepare this tablet.

Ropinirole, its chemical structure, its preparation methods and its therapeutic uses are described in more detail in EP-A-0113964 (see example 2), EP-A-0299602, EP-A-0300614, WO 91/16306, WO 92/00735 and WO 93/23035. Most preferably, the ropinirole tablet is in the form of its hydrochloride salt. Ropinirole is currently marketed as an HCl salt in immediate release tablets for the treatment of Parkinson's disease (see also EP-A-0299602). Ropinirole can be synthesized by the preferred method described in WO 91/16306. The term "ropinirole" as used herein also includes pharmaceutically acceptable salts.

In recent years, significant progress has been made in research in the field of pharmaceutical technology to produce innovative pharmaceutical forms for the administration of active substances in human and veterinary medicine. One of the key features of innovative pharmaceutical dosage forms and / or manufactured formulation systems is the potential targeting of drug (or active ingredient) release to a specific site of action and / or the release of such active ingredients at a pre-programmed rate that can be assessed by appropriate tests " in vitro ".

Other sectors, not only the human health sector, are also interested in these technical areas, namely the veterinary and agricultural sectors, especially with regard to the controlled release of fertilizers, herbicides, insecticides and / or specific protection measures for certain crops.

There are many examples in the field of pharmacy relating to the preparation of pharmaceutical forms capable of releasing an active ingredient (active ingredient) with kinetics of zero order. As is well known to those skilled in the art, this means that the transferred active ingredient is released from the pharmaceutical form at a constant rate over time and for a programmed period of time. In particular, drug release can be expressed by the following empirical relationship:

Mt / M0 = Ktⁿ

The fraction of drug released (Mt / Mo) is proportional to the constant K depending on the diffusion coefficient in the matrix, while the constant n depends on the swelling characteristics and the relaxation rate of the polymer chains at the swelling front. There are many examples of such pharmaceutical forms, for example those listed in S. Dimitriu's "Polysaccharides in medical applications" by M. Dekker, New York 1996.

There are many examples and pharmaceutical uses of dosage forms suitable for various forms of administration, namely oral, transdermal, vaginal and ocular. Obviously, due to the extreme importance and wide application of oral drug delivery, more and more varied approaches relate to the release of the active ingredient in the gastrointestinal tract, such as the OROS system described in US Patent 4,160,020.

Oral pharmaceutical dosage forms described in patents US 4,839,177 and US 5,422,123 (equivalents of EP-A-0226884 and EP-A0432607) are also further advances in this field, which describe the preparation of pharmaceutical forms for oral administration which release the active ingredient at a constant rate. release, i.e. according to the zero-order kinetics (n = 0 in the formula above). In particular, these documents describe the preparation of a therapeutic system comprising, in the simplest form, a hydrophilic matrix containing a drug and suitable excipients, capable of releasing the active ingredient at a variable rate (i.e. with a controlled release rate).

Important components for providing slow active ingredient release are hydrophilic polymers which can gel and are able to swell on contact with water and / or aqueous fluids to form a gel layer from which the active ingredient is released according to Fick-like kinetics.

The therapeutic system described in US 4,839,177 and US 5,422,123 is characterized in that one part of the matrix is ​​covered with an impermeable barrier (obtained with a polymer film that is insoluble in water and aqueous media, as in US 4,839,177), or that the layer of substances and / or mixtures of polymeric substances are applied by pressing (possibly granules obtained according to known methods), whereby impermeability is achieved and / or,

In any case, slowing the release of the drug contained in the matrix from the protected surface over a period of time (as in US 5,422,123). The result is that the active ingredient carried in the hydrophilic matrix is ​​released only from the free surface of the layer containing the active ingredient in direct contact with the dissolving medium. Such a system is characterized in that the active ingredient contained in the pharmaceutical forms is released at a rate that is generally constant over time (release with zero-order kinetics), as stated in the claims of the cited patent specification.

Other tablet formulations have been prepared which release one or more drugs at different release rates (WO 94/06416) by appropriate formulation of the layers in the multilayer tablet. Alternative drug phase release systems have been described using an impermeable membrane to control the time of drug release (US 5,487,901), a full coating of a biodegradable polymeric substance (US 6,027,748), or a more compact layer of a controlled permeation substance (EP-A-0788790). Still other multilayer tablets have been described which show a significant increase in volume upon contact with the stomach contents, resulting in a longer residence time in the stomach (EP-A-0795324).

However, in many treatment procedures, the patient has to take medication for an extended period of time while treating a chronic disease, and must adhere to, sometimes, complex posology regimens, taking two or more pharmaceutical forms within 24 hours. Such complex and varied therapeutic models are poorly accepted and rarely used by non-hospitalized patients; in fact, withdrawals from strict adherence to posology models are very common and well known in the case of outpatients, with such withdrawal being directly proportional to the complexity and number of daily administrations necessary or recommended. For example, in the treatment of chronic diseases, e.g. hypertension, drug administration must be adjusted according to the severity of the pathology and therefore personalized to the specific therapeutic needs of the individual.

It is important for many pathology models that physicians require the availability of pharmaceutical forms with a very different content of the active substance (in order to favor personalization of posology), which, however, can release the drug with a similar or equivalent release rate and kinetics, regardless of the amount of active substance contained.

Thus, the availability of pharmaceutical forms that can release different doses of the same drug at the same or similar rate would provide physicians with a solution to an important therapeutic problem that is socially related to the type of therapy involved. Such dosage forms will allow the use of the drug and biologically active substances in general to be optimized.

It has now been found that the use of a particular formulation and pharmaceutical form which is a multi-layer tablet, preferably having two or three layers, produces a similar or identical release rate, even if the tablet contains very different amounts of the same active ingredient.

The originality of the new produced form, in addition to the morphological and practical characteristics of the new therapeutic system, is presented in the detailed description below.

The invention relates to a controlled release multilayer tablet containing ropinirole, characterized in that it comprises:

(a) one active layer containing: (i) 0.05 - 20% by weight of ropinirole, including its pharmaceutically acceptable salts, (ii) hydrophilic polymeric substances which swell and / or gel and / or erode upon contact with aqueous liquids, (iii) lipophilic substances and (iv) 5 - 50% by weight of excipients, the weight ratio of hydrophilic polymeric substances to lipophilic substances contained in the active layer is in the range from 7: 1 to 1: 1; and (b) one or more barrier layers that limit the release surface of the active layer and contain one or more hydrophilic polymeric substances which swell and / or gel and / or erode on contact with aqueous liquids, lipophilic substances and excipients;

wherein the tablet is optionally coated.

A multilayer tablet in which the active ingredient is ropinirole hydrochloride is preferred.

A multilayer tablet which contains the hydrophilic polymeric substances (ii) in an amount of 30-75% by weight of the active layer is preferred.

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A multilayer tablet that contains lipophilic substances (iii) in an amount of 5 - 55% by weight of the active layer is preferred.

A multilayer tablet is preferred which contains excipients (iv) in an amount of 10 to 40% by weight of the active layer.

A multilayer tablet in which the hydrophilic polymeric substances include a pharmaceutically acceptable, biocompatible and / or biodegradable material, including uncrosslinked polyvinylpyrrolidone, hydroxypropyl cellulose with a molecular weight of 100,000 - 4,000,000, sodium carboxymethylcellulose, carboxymethyl-methylcellulose, hydroxymethyl-methacrylate-hydroxymethyl-methacrylate copolymer 2,000 - 4,000,000, polyethylene glycol with a molecular weight of 200 - 15,000, polyoxyethylene with a molecular weight of up to 20,000,000, carboxyvinyl polymer, poloxamer (polyoxyethylene-polyoxypropylene copolymer), polyvinyl alcohol, glucan, carrageenan, scleroglucan, mannan, galactomannan, gellans, xanthates and / or its alginate acid derivative, polyamino acids, methyl vinyl ether / maleic anhydride copolymer, carboxymethyl cellulose and / or its derivative, ethyl cellulose, methyl cellulose, starch, starch derivative, α-, β- or γ-cyclodextrin and / or a dextrin derivative.

Particularly preferred is such a multilayer tablet in which the hydrophilic polymeric substances in the active layer contain:

(a) one or more of the following substances: hydroxypropyl cellulose with a molecular weight of 100,000-400,000, hydroxypropylmethyl cellulose (HPMC) with a molecular weight of 2,000 4,000,000, ethyl cellulose and methyl cellulose; and (b) sodium carboxymethyl cellulose, carboxymethyl cellulose or derivatives thereof, hydroxypropyl cellulose with a molecular weight of 100,000-4,000,000, carboxyvinyl polymer, carrageenan, xanthan, alginic acid or a derivative thereof, ethylcellulose, methylcellulose and / or maltrodextrin /.

In particular, the hydrophilic polymeric substances in the active layer contain hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose.

Preferably, the hydrophilic polymeric substances in the active layer contain hydroxypropylmethylcellulose with a molecular weight of 20,000 - 500,000 or a viscosity of a 2% aqueous solution at 20 ° C 80,000 - 120,000 mbar.

In particular, the hydrophilic polymeric substances in the active layer contain hydroxypropyl methylcellulose with a molecular weight of 250,000.

Preferably the hydroxypropyl methylcellulose in the active layer is gelling hydroxypropyl methylcellulose.

A multilayer tablet in which the lipophilic substances include natural fat as such, or fully or partially hydrogenated, beeswax, polyoxyethylene beeswax, mono-, bi- or tri-substituted glyceride, glyceryl palmitate, glyceryl palmitate, glyceryl behenate, diethylene glycol glycearate, diethyleneglycol stearate is preferred. polyethylene, polyoxyethylene glycol palmitate, glyceryl monopalmitate, cetyl palmitate, polyethylene glycol palmitate stearate, glyceryl mono- or dibehenate, polyoxyethylene fatty alcohol bound fatty alcohol, cetyl alcohol, stearic acid, saturated or unsaturated fatty acid or its hydrogenated derivative and / or hydrogenated castor oil.

Preferably, the lipophilic substance present in the active layer is selected from hydrogenated castor oil and glyceryl behenate.

Preferably, the multilayer tablet comprises (i) ropinirole and / or its pharmaceutically acceptable salts active ingredient in an amount of 0.05-20% by weight of the active layer, (ii) a hydrophilic polymeric substance consisting of hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose. (iii) a lipophilic substance, which is hydrogenated castor oil or glyceryl behenate and (iv) excipients in an amount of 5 - 50% by weight of the active layer, the weight ratio of hydrophilic polymeric substances to lipophilic substances contained in the active layer is in the range from 7: 1 to 1: 1 .

A multilayer tablet in which the weight ratio of hydrophilic swelling and / or gelling and / or eroding polymeric substances to lipophilic substances contained in the barrier layer is in the range from 1: 1 to 7.5: 1 by weight ratio is preferred.

Preferably, the multilayer tablet comprises ropinirole and / or its pharmaceutically acceptable salts in an amount up to 12.0 mg, based on the amount of ropinirole base.

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It is particularly preferred that the multilayer tablet contains ropinirole and / or a pharmaceutically acceptable salt thereof in an amount of 0.75-12.0 mg, based on the amount of ropinirole base.

A multi-layer tablet having one or more barrier layers applied to one or both surfaces (bases) of the active layer is preferred, and more preferably the barrier layer is applied to both surfaces (bases) of the active layer.

A multilayer tablet is preferred, wherein the release of ropinirole during the first hour after oral administration or immersion in aqueous fluids occurs essentially only from the surface of the tablet not covered by one or more barrier layers.

A preferred multilayer tablet consists of an active layer and two barrier layers, one barrier layer is applied to each surface (base) of the active layer, with a 150 mg active layer consisting of up to 12 mg of ropinirole hydrochloride (measured as the amount of ropinirole as bases), 41% HPMC type 2208 (100,000 cP), 10% sodium carboxymethyl cellulose, 5% maltodextrin, 10% hydrogenated castor oil, 1% magnesium stearate, 0.6% colloidal silica and lactose monohydrate in sufficient amount, and barrier layers of 120 - 170 mg are essentially composed of 23.6% mannitol, 25% glyceryl behenate, 5% polyvinylpyrrolidone, 1% magnesium stearate, 0.4 % colloidal silica, HPMC type 2208 (100,000 cP), and optionally a dye in sufficient amount, the controlled release tablet optionally being coated with about 13.80 mg of coating agent.

A multi-layer tablet having a single barrier layer weighing 170 mg and a second barrier layer weighing 140 mg is preferred.

Preferably, the multilayer tablet is film coated with about 13.80 mg of coating agent.

Preferably, the multilayer tablet comprises one barrier layer weighing 130 mg and a second barrier layer weighing 120 mg, preferably the tablet is uncoated.

Preferably, the barrier layers contain a dye, in particular yellow ferric oxide.

Preferably, the multilayer tablet contains in the active layer an amount of ropinirole hydrochloride in an amount of 0.75-12 mg, measured as the amount of ropinirole base.

Preferably, the multilayer tablet is produced by compressing the powder or granular mixture at a pressure of 98.07-490.33 MPa.

The multilayer tablet as defined above is for use in the treatment of Parkinson's disease.

The invention further relates to the use of ropinirole for the preparation of a controlled release multilayer tablet as defined above for the treatment of Parkinson's disease.

Preferably, a single controlled release multilayer tablet is administered once a day to a human in need of such treatment.

The multilayer tablets of the invention are able to provide substantially equivalent (or identical) release kinetics for the same active ingredient when formulated in different amounts in the layer containing the active ingredient in the multilayer tablet. The described pharmaceutical tablets preferably release the active ingredient contained in a programmed manner, preferably there is no dose shedding, either, and can therefore meet the specific therapeutic needs of the gradual and controlled release of the active ingredient.

In certain embodiments, a tablet of the invention can be characterized as a tablet containing (i) ropinirole in an amount of 0.05-20% by weight of the active layer, (ii) a hydrophilic polymeric substance in the form of hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose, (iii) a lipophilic substance in the form of hydrogenated castor oil or glyceryl behenate and (iv) excipients in the amount of 5 - 50% by weight of the active layer, wherein the weight ratio of hydrophilic polymeric substances to lipophilic substances is in the range from 7: 1 to 1: 1.

In tablets of the invention, the amount of ropinirole present, including its pharmaceutically acceptable salts, may be up to 12.0 mg, preferably 0.75-12.0 mg, measured as the amount of ropinirole base, i.e. excluding any amount of acid (e.g. hydrochloric acid, HCl) added to form any ropinirole salt. The amount of ropinirole present, including pharmaceutically acceptable salts, may be up to 12.0 mg, preferably 0.75-12.0 mg, measured as the amount of ropinirole base, per 150 mg of active layer present. See examples 1 to 6 below.

Multilayer tablets may be produced as bilayer tablets, trilayer tablets or tablets with more layers, if desired. At least one layer will contain

The active ingredient released from the tablet, and at least one layer will be a barrier or support layer with respect to the layer containing the active ingredient. Possible types of multi-layer tablet structures are shown in Figures 1-9. The tablets may have an overall substantially circular cross section, or they may have a more oval cross section or any other suitable geometric shape, e.g. rectilinear. The tablet may also be shaped as a caplet (capsule tablet). As can be seen, there are many potential layer systems in multi-layer tablets.

The layer containing the active ingredient may be referred to as the active layer, although it will be appreciated that more than one active ingredient may be formulated into a tablet of the present invention. A layer that is generally free of active ingredient may be referred to as a barrier layer or a support layer.

A simple two-layer tablet is shown in Figure 1, where one side (dotted) surface of the active ingredient-containing layer is covered by a barrier (dotted) layer. A variation of this structure is shown in Figure 2 where two barrier layers cover both of the exposed side surfaces of the layer containing the active ingredient. In Figure 3, a single barrier layer covers one side surface and one side of the active layer. The barrier layer is shown as being in the form of a ring in Fig. 4 surrounding the active core, and Fig. 5 shows an active core composed of two active layers surrounded by a barrier layer ring.

Fig. 6 shows a three-layer tablet in which there is a first barrier layer 3 with an exposed upper side surface and sides that are adjacent to the second active layer 2 with both side surfaces covered and a side of the layer exposed, which in turn is adjacent to the second active layer 1. the bottom side surface is exposed and the side is exposed. The two active layers may contain different active ingredients or the same active ingredient in different amounts. Fig. 7 shows an alternative embodiment of the embodiment of Fig. 6, wherein the active substance layer 5 is completely inside the barrier layer 6 and the second active substance layer 4. Figure 8 shows a similar three-layer tablet in which a barrier layer 8 is provided between the two active ingredient-containing layers 9 and 7.

Another structure of the three-layer tablet (caplet) is also shown in Figure 9, wherein the tablet has two outer barrier layers 10, 12 and an active ingredient layer 11 sandwiched between the barrier layers.

In certain tablet configurations, the barrier layer may also contain the active ingredient such that it functions as a barrier layer with respect to the first active ingredient-containing layer, but is itself the active ingredient-containing layer. Generally, in such embodiments, the active ingredients in the active layers are different in different layers, although systems are conceivable in which the same active ingredient is present in different active layers in different amounts.

The barrier layer (s) is (s) to limit the release surface of the active layer in order to allow the contained active ingredient to be released only through the uncovered surface in contact with the dissolving medium and / or biological fluids according to kinetics that can be programmed in vitro by precise methods which will be explained in the following examples of the invention.

The described tablets can be formulated into a pharmaceutically active ingredient suitable for oral administration in the form of tablets. The active substance is therefore a pharmaceutical (drug) for therapeutic use, but such substances also include substances to be administered for non-therapeutic purposes, such as diagnostics, or for nutritional purposes.

Preferably, the active ingredient may be a substance intended for the treatment of chronic diseases, e.g. cardiovascular drugs, antiarrhythmics, cardiac stimulants, vasodilators, calcium antagonists, antihypertensive agents, e.g. centrally and peripheral anti-adrenergic agents or substances that act on the arteriolar muscles, analgesics, substances that act on the renin-angiotensin system, antihypertensive agents in combination with diuretics, anti-Parkinson agents, diuretics and drugs for the treatment of Alzheimer's disease, antihistamines and / or anti-asthma medications.

Examples of active ingredients that can be used in such pharmaceutical forms are: propranolol, atenolol, pindolol, ropinirole, prazosin, ramipril, spirapril, spironolactone, metipranolol, molsidomine, moxonidine, nadolol, peroxolol, levodopa, metoprolol, timolol.

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Analgesics include, but are not limited to, steroidal anti-inflammatory drugs, opioid analgesics, and non-steroidal anti-inflammatory drugs (NSAIDs). The analgesic substance may be a non-steroidal anti-inflammatory drug (NSAID) such as acetylsalicylic acid, salicylic acid, indomethacin, ibuprofen, naproxen, naproxen sodium, flubiprofen, indoprofen, ketoprofen, piroxicam, diclofenac, cetoprofen, their sodium diclofenac, their sodium pharmaceutically acceptable salts and / or derivatives or mixtures thereof.

Other suitable analgesic substances include, but are not limited to, opioid analgesics such as alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocin, desomorphine, dextromoxorhydramide, dipromidine, dextromorphine, dipromorphine, desomorphine, , dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazocin, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levalorphan, levorphanol, levofenacilmorphan, lofentanil, meperidine, meptainol, metazocin, methadone, methopone, morphine, myrofin, nalbuphine, nalorphine, normphetine, norpuphine opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, fenazocin, phenoperidine, piminodine, pyramid, proheptazine, promedol, properidine, propiram, propoxyphene, Sufentanil; tramadol, tilidine and pharmaceutically acceptable salts and / or derivatives or mixtures thereof.

The antihypertensive drugs may include diltiazem, trapidil, urapidil, benziodarone, dipyridamole (dipyridamole), lidoflazine, naphthydrofuryl oxalate, perhexseline maleate, oxyphedrine hydrochloride. Antihistamines and / or anti-asthma agents may include ephedrine, terfenadine, theophylline, or chlorpheniramine.

Matrices can be prepared containing any type of active ingredient for which pharmaceutical forms capable of also releasing very different amounts of active ingredient with the same release kinetics may be needed.

The active ingredient contained in the described tablets may have a very wide water solubility range, e.g. 0.01-3000 g / l, preferably 10-1000 g / l (e.g. ropinirole has a solubility of 133 g / l) or 0.01 - 100 g / l.

The active ingredient is preferably present in an amount of 0.05-50% by weight of the active layer; more preferred ranges of active ingredients are 0.05-40%, 0.05-30%, 0.05-10%, 0.05-20%.

For the formation of such an active layer, natural or synthetic hydrophilic polymer substances can be used which are biocompatible and / or biodegradable and pharmaceutically acceptable substances, e.g. polyvinylpyrrolidone, in particular non-cross-linked polyvinylpyrrolidone (e.g. with a molecular weight of 30,000 - 400,000), hydroxypropylcellulose with a mass molecular weight 100,000 - 4,000,000, sodium carboxymethylcellulose (e.g. non-cross-linked, e.g. typical molecular weight 90,000 - 700,000), carboxymethyl starch, potassium divinylbenzene methacrylate copolymer, hydroxypropylmethylcellulose with a molecular weight of 2,000 - 4,000,000, polyethylene glycols of various molecular weights, preferably 200 - 15,000 (more preferably 1,000 - 15,000) and polyoxyethylenes of more preferably 20,000 - 15,000 400,000 - 7,000,000), carboxyvinyl polymers, poloxamers (polyoxyethylene-polyoxypropylene copolymer), polyvinyl alcohols, glucans, carrageenans, scleroglucans, mannans, galactomannans, gellans, xanthates, alginic acid and derivatives (e.g. sodium or calcium alginate, propylene glycol alginate), polyamino acids (e.g. gelatin), methyl vinyl ether / maleic anhydride copolymer, carboxymethyl cellulose and derivatives (e.g. calcium carboxymethyl cellulose), ethyl cellulose, methyl cellulose, starch and starch derivatives, α-, β- or γ-cyclodextrin, and dextrin derivatives (e.g. dextrin) in general. A hydrophytic polymeric substance is therefore a substance that can be defined as a controlled release polymer or a polymeric substance that is capable of providing a controlled release (CR).

More preferably, in order to achieve a favorable controlled release of the active ingredient, the hydrophilic polymeric substances in the active layer include one or more of the following: hydroxypropyl cellulose with a molecular weight of 100,000 - 4,000,000, hydroxypropyl methylcellulose (HPMC) with a molecular weight of 2,000 - 4,000,000 (more preferably with a molecular weight of 10,000 - 1,500,000, even more preferably with a molecular weight of 20,000 - 500,000 and most preferably with a molecular weight of about 250,000), ethyl cellulose or methylcellulose. The most preferred controlled release polymer is HPMC.

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Hydrophilic polymeric substances such as sodium carboxymethyl cellulose and / or calcium carboxymethyl cellulose which act as viscosity enhancing agents / polymers or "cage forming" components are also preferred ingredients of eg an active layer. The inclusion of these viscosity-enhancing polymers in the active layer is advantageous as they help to reduce the "dose-dropping" effects occasionally encountered with soluble actives (e.g. ropinirole) so that a significantly smaller amount of the active ingredient can be released from the active layer in the first (for example) hour after oral administration. Thus, it is therefore preferred that the hydrophilic polymeric substances in the active layer comprise sodium carboxymethyl cellulose, carboxymethyl cellulose or a derivative thereof (e.g. calcium carboxymethyl cellulose), hydroxypropyl cellulose with a molecular weight of 100,000 - 4,000,000, carboxyvinyl polymer, carrageenan, xanthan, alginic acid or a derivative thereof (e.g. sodium or calcium alginate, propylene glycol alginate), ethyl cellulose, methylcellulose and / or dextrinose, and / or dextrin. Most preferred for this purpose is sodium carboxymethylcellulose (NaCMC) (e.g. non-cross-linked, e.g. with a typical molecular weight of 90,000-700,000). The invention also encompasses the use of other equivalent polymers capable of acting as tackifiers and / or cage forming components.

More preferably, the hydrophilic polymeric substances in the active layer include the above-mentioned preferred controlled-release polymers and the above-defined viscosity-increasing polymers. Thus, it is preferred that the hydrophilic polymeric substances in the active layer contain one or more substances from the groups (a) and (b) mentioned above.

Thus, while the controlled-release polymer such as HPMC still swells and / or gels gradually about one hour after oral administration of the tablet, and may be less effective in controlling the release of soluble actives such as ropinirole, from the active layer, a viscosity-increasing polymer (b), such as sodium carboxymethyl cellulose (NaCMC), reduces the release of the active ingredient from the active layer. Without wishing to be bound by theory, it is believed that ionic viscosity enhancers such as NaCMC can also interact with hydroxypropyl groups, e.g. in HPMC, synergistically increasing the rate of hydration and swelling of the HPMC leading to greater gel strength.

Thus, the most preferred combination is one in which the hydrophilic polymeric substances in the active layer contain (or are) HMPC and sodium carboxymethyl cellulose, especially when the active ingredient has high (e.g. 10-1000 g / l) water solubility, such as ropinirole.

Preferably, the hydrophilic polymeric materials have an HLB value of at least 10 (see A. Gennaro and J. Remington, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Company, Easton, Pa., 304 (1990) and WC Griffin, J. Soc. Cosmetic. Chemists, Vol. 1, pp. 311, 1949 for HLB values ​​and their measurements). Such hydrophilic polymeric substances constitute 1-75% by weight of the active layer, but are preferably present in an amount of 5-65% and / or 30-75%, more preferably 43-75% or 43-67% or 43-65%. Any HPMC present in the active layer is preferably present in an amount of about 40-63% by weight of the active layer. The above-mentioned viscosity-increasing polymers, such as sodium carboxymethylcellulose, are optionally preferably present in an amount of up to 20% by weight of the active layer, more preferably (especially in the case of NaCMC) 3-20%, 5-20%, 7-15 %, or about 10 % by weight of the active layer.

For all of the polymers mentioned, various types are commercially available with different chemical, physical, solubility, and gelling properties. In particular, with respect to hydroxypropyl methylcellulose, different types can be used which differ in molecular weight (molecular weight 1,000-4,000,000, preferably 2,000-4,000,000, more preferably 10,000-15,000,000, even more preferably 20,000-500,000 and most preferably around 250,000) and with different degrees of substitution. These types of hydroxypropyl methylcellulose have different characteristics and are mainly erodable or can gel depending on the viscosity and degree of substitution (DS) in the polymer chain. Gelling HPMC (e.g., Methocel K species) are preferred over eroding HPMC (e.g., Methocel E species). Polyethylene glycols and polyoxyethylenes exhibit identical activity: in fact, different hydrophilic and gelling properties correspond to different molecular weights.

The molecular weight of polymers and the viscosity of 2% polymer solutions can be directly correlated ("METHOCEL ™ in Aqueous Systems for Tablet Coating", p. 12, The Dow Chemical Company -www.dow.com - METHOCEL ™ is a trademark of The Dow Chemical Company) wherein the viscosity of the polymer is defined as the viscosity of a 2% aqueous solution at 20 ° C, measured in mPa · s. Viscosity is measured in pascal seconds (SI units) or in poise (cgs units), with 1 cP = 10^-3 Bye ^ s. For example, METHOCEL ™ K100M has an approximate weight

A molecular weight of 246,000, corresponding to a 2% solution viscosity of 100,000 mPa · s (based on an average viscosity of 80,000 - 120,000 mPa · s); METHOCEL ™ K4M has an approximate molecular weight of 86,000 corresponding to a 2% solution viscosity of 4,000 mPa · s; and METHOCEL ™ K100LV has an approximate molecular weight of 27,000, corresponding to a 2% solution viscosity of 100 mPa · s. Therefore, the preferred molecular weight ranges of the polymeric substances, e.g. Hydroxypropyl methylcellulose polymers can also be defined in terms of viscosity.

One preferred viscosity range for the hydroxypropyl methylcellulose polymers defined above may be 50 - 150,000 mPa · s, suitably 80,000 - 120,000 mPa · s (e.g. K100M, as in the active and barrier layers in Examples 1-9). This is true for both the active layer (s) (discussed above) and the barrier / support layer (s) (discussed below).

In an alternative embodiment, the viscosity range for the hydroxypropylmethylcellulose polymers in the active and / or barrier layer (s) may be 50-25,000 mPa · s (including Methocel K4M, K15M, K100LV) in order to achieve higher release rates. In this embodiment, preferably some or all of the HPMC polymers have a viscosity in the range 1000-25000 mPa · s (including Methocele K4M and K15M but not K100LV or K100M). More preferably, HPMC polymers with a viscosity in the range 1000-25000 mPa · s are present in the active or barrier layer in an amount of 5-50% by weight of the active or barrier layer. Specifically, Examples 10 and 11 below used 10% and 40% by weight of such HPMC (K4M) polymer in the barrier layers, respectively, which provides a slightly faster in vitro release profile than about 45% by weight of K100M HPMC present in the barrier layers in Examples 1- 6 and 7-9, the active ingredient, e.g. ropinirole, amongst others, migrates faster through the barrier layers. Preferably the proportion of low viscosity HPMC, i.e. a viscosity of 50 to <1000 mPa · s (including Methocel K100LV), contained in the active or barrier layers is less than 30% by weight of this layer - e.g. in example 10 it is 20% by weight of such HPMC (K100LV) as well as 10 wt% HPMC K4M in the barrier layer. Up to 30% low viscosity HPMC in the active or barrier layer can increase water uptake and aid gelling by increasing matrix viscosity and reducing release rate, but higher amounts are not preferred.

In an alternative embodiment, the invention relates to a tablet as defined above, wherein the active layer comprises a polymeric substance with slow swelling and / or gelling and / or erosion and / or solubility properties.

A fundamental feature of the tablets according to the invention is that lipophilic substances, e.g. natural fats (coconut, soybean, cocoa) as such, or fully or partially hydrogenated, beeswax, polyoxyethylene beeswax, mono fats are used to form the active ingredient layer and barrier layers -, bi- and tri-substituted glycerides, glyceryl palmitostearate, glyceryl behenate (glyceryl tribehenate C69H134CO6, e.g. Compritrol 888, where behenic acid = docosanoic acid C21H43COOH), diethylene glycol palmitostearate, polyethylene glycol stearate, polyethylene glycol palmitostearate, polyoxyethylene glycol palmitostearate, (glyceryl monopalmitostearate or glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate, glyceryl monopalmitostearate. , fatty alcohols related to polyoxyethylene fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, hydrogenated castor oil and lipophilic substances in general. In certain preferred embodiments of the invention, the lipophilic substances are selected from hydrogenated castor oil and glyceryl behenate.

Preferably the lipophilic substances have an HLB value of less than 10, more preferably less than 5.

Preferably, lipophilic substances constitute 1-70% by weight of the active layer, but are preferably present in an amount of 5-55%, more preferably 5-35%.

The weight ratio of hydrophilic polymeric substances and lipophilic substances in the layer containing the active ingredient is from 10: 1 to 0.5: 1 (i.e. in the range from 10: 1 to 0.5: 1), suitably from 10: 1 to 1: 1 (i.e. in the range from 10: 1 to 1: 1), preferably from 7: 1 to 1: 1 (i.e. in the range from 7: 1 to 1: 1).

In addition to the above-mentioned hydrophilic polymers and lipophilic substances, substances of a lipophilic and / or amphiphilic nature can be used in the preparation, the hydrophilic part of which may be glycerol or other polyalcohols molecules, or polyethylene glycol (PEG) molecules with a molecular weight of 100-10,000, while some lipophilic are unsaturated and / or saturated fatty acids in the form of hydrogenated vegetable oil. The connection of the hydrophilic part with the lipid chain is achieved by esterification or partial alcoholysis reactions of hydrogenated vegetable oils with PEG or glycerin or other polyol molecules. This is how it receives

Compounds exhibit varying degrees of hydrophilicity, which can be assessed by measuring the hydrophilic-lipophilic balance (HLB). There are triglycerides with HLB 1-2, diglycerides with HLB 2-3, monoglycerides with HLB 3-4, PEG diesters with HLB 6-15, PEG monoesters with HLB 10-17. reduces the lipophilic tendency. The tablets according to the invention may therefore also contain polymeric substances of a lipophilic nature.

Finally, auxiliaries customary in pharmaceutical technology may be used, e.g. diluents, binders, lubricants, glidants and non-stick agents, e.g. starch, mannitol, lactose, sorbitol, xylitol, talc, stearic acid, sodium benzoate, magnesium stearate. , colloidal silica, maltodextrin and other excipients known to those skilled in the art.

In order to facilitate the penetration of water and / or aqueous fluids in the layer or core, hydrophilic diluents, e.g. mannitol, lactose, starches of various origins, sorbitol, xylitol, or substances with wetting and / or penetration enhancers are preferably incorporated into the formulation. water in a solid.

In addition, diluents, binders, lubricants, buffers, release agents, glidants and softeners, as well as others capable of imparting the desired characteristics to the layer, may be used, as will be illustrated in more detail in the examples below.

Such auxiliaries are preferably used in an amount of 5-50%, preferably 10-40% or 20-50% or 20-35% by weight of the active layer. The weight ratio of active ingredient (i) to excipient (iv) in the active layer may range from 0.001: 1 to 4: 1, conveniently from 0.003: 1 to 3: 1.

The polymeric substances used to form the barrier layer in combination with other adjuvants can form a barrier (applied by compression) which is impermeable to the transported active substance in the lower layer for a time which is strictly dependent on its composition and can range from 1 hour to about 20 - 24 hours or more. In such a case, the release of the active substance in given periods (e.g. during the first hour after oral administration / immersion in aqueous fluids) only occurs from the non-barrier surface of the tablet. "Impermeability" should be interpreted accordingly. Preferably, during the first hour after oral administration or immersion in aqueous fluids (e.g. water), release of the active ingredient occurs essentially only from the non-barrier coated surface of the tablet.

In order to test the impermeability of the barrier layer upon release of the active ingredient, various suitable tests can be developed by those skilled in the art of formulating pharmaceutical tablets. However, one such test may be based on the selective coating of free active layer surfaces with a suitable substance such as an enteric coating (eg "Eudragit") or a waxy substance (eg beeswax) such that normal active ingredient release does not take place through these surfaces. An in vitro dissolution test can then be performed in which samples of the dissolving fluid can be withdrawn at appropriate time points. In this way, it is possible to determine the point in time at which the active ingredient is released through the barrier layer due to the interaction of the constituent substances of the barrier layer with the aqueous environment (i.e. the time point at which the polymers of the barrier layer allow release). Alternatively, free surfaces of the barrier layer (s) may be selectively coated as above and a dissolution test performed. The resulting release profiles will be those for uncoated tablets up to the point in time at which the active ingredient is able to pass through the barrier layer and be released from the uncoated tablet.

As noted above, the barrier layer may be applied to one or more of the free surfaces of the active layer in the tablet. Generally, the barrier layer will form a layer covering one or more side surfaces of the active layer. In a preferred embodiment of the invention, tablets are prepared wherein one or more barrier layers are used to cover one or both of the surfaces or bases of the active layer. Thus, such arrangements result in a two-layer or three-layer tablet.

Natural synthetic hydrophilic polymeric materials useful in the formulation of the barrier layer can be selected from those listed for the production of the active layer. Such polymeric substances may be present in an amount of 5-90%, based on the total weight of the layer, preferably 25-85%.

PL 202 689 B1

These polymeric substances, when used alone or mixed with each other and mixed with lipophilic substances, are able to provide impermeability to the release of the contained active substance from the underlying layer for a period which can be from 1 hour to about 20-24 hours or more, for depending on the composition.

For the formation of the barrier layer, such lipophilic substances can be selected from those listed with regard to the formation of the active layer. Such lipophilic substances may be present in an amount of 5-70%, based on the total weight of the layer, preferably 5-55%.

The weight ratio of hydrophobic swellable and / or gelling and / or eroding polymer substances to lipophilic substances contained in the barrier layer may range from 1: 1 to 7.5: 1, suitably from 1.5: 1 to 4: 1, preferably from 2: 1 to 3.5: 1.

The barrier layer (s) applied by pressing may have a thickness of 0.1 - 4.5 mm. The matrix can be made by compacting powder or granular mixtures, e.g. by blending followed by dry pressing, or by wet granulating followed by pressing, preferably at a pressure of 98.07-490.33 MPa.

In general tabletting may be direct compression, i.e. compressing a mixture of dry powders, but this may occasionally cause quality problems such as segregation, poor flow etc. These difficulties can be overcome by using granulation methods for all or part of the blend.

Granulation is the process by which powder particles agglomerate to form granules. It can be run for:

1. improving the flowability of the powder mixture,

2. preventing segregation of constituent powders (improving homogeneity),

3. improving the ironing characteristics,

4. achieving a compaction of the powder mixture and / or

5. achieving particle size / shape / hydrophilicity change.

The tablet of the invention may be manufactured by dry granulation. Dry granulation is granulation by pressing the powders by agglomeration or roller compression. It is essentially a compaction process.

Caking occurs when a green compact (body) is matched to a given weight / thickness for a given body diameter. These lumps are then reduced with a grating or grinding mill to produce granules of the desired particle sizes / ranges.

In the case of roller compaction, i.e. in the compression device, the powder mixture is forced by a screw conveyor between 2 rollers (which can be smooth or grooved). The compaction of this mixture is controlled by the speed of feeding to the rollers and the force of hydraulic pressing of the rollers. The resulting compacted blend (called a ribbon or belt) is ground in a grating or grinding mill to produce granules of the desired sizes / size ranges.

When dry granulation is used, the adjuvants often differ slightly from those used in wet granulation. For example, instead of lactose monohydrate (often used in wet granulation), spray dried lactose is preferably used, preferably containing amorphous lactose (e.g. Fast-Flo lactose, Seppic, Paris, France).

However, the tablet of the invention is preferably produced by wet granulation. Wet granulation is the most widely used granulation method and involves compacting and / or agglomerating the powder by introducing a fluid / granulation medium into the powder mixture. Wet granulation may be water or solvent based, e.g. based on organic solvents. The shear depends on the agitator / blade speed of the powder granulator. Various mixer designs are available, e.g .:

High shear wet (Fielder rotating) Slight wet shear (Low shear rotating (planetary mixer)) Slight wet shear drum (spraying into drum mixer , optionally containing an intensifying rod), extruding (the wet solid is pressed through a defined screen) rotary granulators (spheronization, marumerization - rotating disk or tank walls) fluidized bed spray granulation, or dry spray granulation.

PL 202 689 B1

In formulating such a compression-applicable barrier layer, optional auxiliaries, in particular diluents, include those conventionally used in the preparation of solid forms. For example, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid, polyethylene glycols and / or colloidal silica may be used.

In addition, diluents, lubricants, anti-stick and glidants and other substances capable of imparting the desired characteristics to the layer may be used, as is better illustrated in the examples given below. Other possible ingredients include substances capable of giving a color to the final layer of a tablet made and formulated in a multilayer tablet, e.g. iron oxide (yellow ferric oxide).

In addition, the finished tablets may be coated by a coating process and / or any other process well known to those skilled in the art. An example of a coating is "OPADRY OY-S-28876 WHITE". OPADRY OY-S-28876 WHITE contains 63% HPMC 2910 6cP, 7% PEG 400, 30% TiO2. Red / pink (0.01-0.25%) and / or yellow (0.1 to 1.5%) dyes (iron oxides) can also be added, the amount of HPMC is 61-66%. The alternative blue coating each contain 31-32% HPMC 2910 3cP and HPMC 2910 5cP, 8% PEG400, 23-24% TiO2, 1% polysorbate and 4-5% indigotine as the blue dye.

A color layer or coating of gastro-resistant enteric-soluble polymeric substance may also be applied to the finished tablets to ensure that the system is activated only after the tablet has reached the duodenal-intestinal tract. Pharmaceutical systems of the latter type can be used to prepare tablets that are specifically designed to release the active ingredient downstream of the intestinal tract, i.e. at the level of the colon. To achieve gastric resistance, polymeric substances such as cellulose acetate phthalate, cellulose acetate propionate, cellulose trimellitate, polymers, and acrylic and methacrylic copolymers with different molecular weights and pH dependent solubilities can be used. Such substances can be applied to the finished pharmaceutical form (active layer and barrier layer (s)) by a known coating process using organic solvent solutions or aqueous dispersions, by spraying or spraying in a fluidized bed. Such gastric-resistant and enteric-soluble substances may likewise be used in conjunction with release-retarding polymers.

One of the advantages of the solution according to the invention is that it is possible to obtain a therapeutic system using currently used manufacturing technologies, so that the system can be manufactured immediately on an industrial scale.

One preferred tablet form according to the invention is the tablet as described above, in which the active layer consists of components (i) - (iv), the active ingredient is present in an amount of 0.05-20% by weight of the active layer, excipients are present in an amount of 5 - 50% by weight of the active layer, the weight ratio of hydrophilic polymeric substances to lipophilic substances being in the range from 7: 1 to 1: 1.

Alternatively, the active layer consists essentially of components (i) - (iv), wherein the active ingredient is present in an amount of 0.05-20% by weight of the active layer, excipients are present in an amount of 5-50% by weight of the active layer, with whereby the weight ratio of hydrophilic polymeric substances to lipophilic substances is in the range from 7: 1 to 1: 1.

In certain preferred embodiments, the hydrophilic polymeric material may be hydroxypropylmethyl cellulose with a molecular weight of 2,000 - 4,000,000, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose.

The invention makes it possible to carry out a method of treatment using the tablet described herein by administering it to a patient / human in need thereof. In particular, the disease to be treated is Parkinson's disease, wherein an active ingredient containing or constituting ropinirole or another therapeutic agent is used to treat the condition. According to such methods, especially with regard to ropinirole, one or more multi-layer tablets may be administered once daily to a human in need of such treatment, or a single multi-layer tablet may be administered once daily. The inventive controlled release tablet of ropinirole is expected to perform better compared to the commercial immediate release (IR) formulation of ropinirole as it should provide a more constant and / or lower systemic concentration / Cmax over 24 hours, eliminating the need for taking ropinirole three times a day as with the IR tablet and should ensure that certain side effects are avoided, which may occur with the administration of ropinirole IR. See in particular a preferred release of about 24 hours

The in vitro method described, inter alia, for ropinirole in Examples 1-6 below: it is nearly optimal in Parkinson's disease.

The invention is described below with reference to the following examples and figures, which are given merely to illustrate the invention. It is described with reference to a number of figures, where:

Fig. 1 is a cross-sectional view of a two-layer tablet, the barrier layer is indicated by hatching and the active substance-containing layer by dotting.

Fig. 2 is a cross-sectional view of a three-layer tablet that has upper and lower barrier layers and a central active layer.

Fig. 3 shows a cross-sectional view of a two-layer tablet in which the barrier layer coats the side surface and the side of the active layer.

Fig. 4 is a cross-sectional view of a bilayer tablet wherein the barrier layer is present as a ring around the active core.

Fig. 5 is a cross-sectional view of the tablet of Fig. 4, in which the active core consists of two different active layers.

Fig. 6 shows a cross-sectional view of a three-layer tablet in which a barrier layer 3 is applied to an active layer 2 which in turn is applied to an active layer 1.

Fig. 7 shows a cross-sectional view of a three-layer tablet in which a first active layer 5 is contained in a barrier layer 6 and a second active layer 4.

Fig. 8 shows a cross-sectional view of a three-layer tablet in which a barrier layer 8 is provided between active layers 9 and 7.

Fig. 9 is a top, side and end view of a three-layer caplet in which the active ingredient layer is located between barrier layers 10, 12; it is shown in cross-section along the line XX.

Fig. 10 shows the dissolution profiles of comparative, repeat batches at doses of 0.75 mg ropinirole, determined as effective free base, for testing the effect of coating on release - the results for the POOK39E tablet are shown as "□", for the POOK40E tablet as "◊". for the POOK41E tablet it is shown as "Δ", for the C511 tablet it is shown as "♦" for the C519 tablet and as "▲" for the C529 tablet. Results are shown as percent drug released (%) over time (hours).

Fig. 11 shows the dissolution profiles of comparative, repeat batches at 6 mg ropinirole effective free base doses to test the effect of coating on release - the results for the POOK45E tablet are shown as "□", for the POOK46E tablet as "◊" for the tablet POOK47E is shown as "Δ", tablet C530 is shown as "", tablet C531 is shown as "♦" and tablet C532 is shown as "▲". Results are shown as percent drug released (%) over time (hours).

Fig. 12 shows the dissolution profiles of comparative, repeat batches at mg doses of ropinirole, determined as effective free base, for testing the effect of coating on release - the results for the POOK42E tablet are shown as "□", for the POOK43E tablet are shown as "" for the POOK44E tablet. is shown as "Δ", for tablet C512 it is shown as "", for tablet C534 it is shown as "♦" and for tablet C535 it is shown as "▲". Results are shown as percent drug released (%) over time (hours).

Figure 13 shows the dose effect of the coated tablets, shown as a comparison of the dissolution profiles of ropinirole at doses of 0.75 mg, 6 mg and 12 mg, determined as free base (repeat batch results). Results are shown as percentage of drug released (%) over time (hours) with C511, C519 and C529 tablets with 0.75 mg ropinirole shown as "-", C530, C531 and C532 tablets with 6 mg ropinirole shown as "------" and tablets C512, C534 and C535, with 12 mg of ropinirole, are shown as "------".

Example 1. Single, triple layer tablet systems - 0.75 mg of ropinirole

In Example 1, the first layer was the "barrier" layer (130 mg), the second (slow release) layer contained 0.86 mg of ropinirole hydrochloride corresponding to 0.75 mg of base; the third layer was the "barrier" layer (120 mg).

1 (a) Preparation of granules used to form slow release container layer containing 0.86 mg of ropinirole hydrochloride corresponding to 0.75 mg of base.

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<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 0.75 mg of base</td><td>0.86 mg</td>

<td>Hydroxypropyl methylcellulose (HPMC) (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 (41 wt.%)</td>

<td>Sodium Carboxymethyl Cellulose (NaCMC) (Blanose 9 M31XF)</td><td>15.00 mg (10 wt.%)</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg (5 wt.%)</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>47.74 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg (10 wt.%)</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg (1 wt.%)</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

The active layer contained a total of 51% by weight of gelling, swelling and / or eroding hydrophilic polymers (HPMC + NaCMC), or 56% by weight when it contained maltodextrin.

Ropinirole and part of the lactose were mixed for 20 minutes in a suitable mixer-granulator (Niro-Fielder PMA type). Hydroxypropyl methylcellulose, sodium carboxymethylcellulose, hydrogenated castor oil, maltodextrin and the remainder of the lactose were added and mixed for 10 minutes, then wetted with water (about 30% by weight of products used). The obtained granulate was dried in a fluid bed dryer (Niro-Fielder TSG 2 type) until a constant weight was obtained. The granulate was then passed through a 0.800 mm sieve of an oscillating granulator. Silica was added and the mixture was mixed in a cubic mixer for 20 minutes, then magnesium stearate was added and mixed for a further 10 minutes. In this way, a granulate (granulate 1 (a)) with good slip and good compressibility was obtained. The granulate was compressed as described below.

1 (b) Preparation of granules to form barrier layers

<td>Ingredient</td><td>Quantity</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>44.76% (or 44.75%)</td>

<td>Mannitol (C. Erba)</td><td> 23,60%</td>

<td>Glyceryl beheniate (Compritol 888 Gattefosse, St. Priest, France)</td><td> 25,00%</td>

<td>Polyvinylpyrrolidone (PVP) (Plasdone® K29-32, ISP)</td><td> 5,00%</td>

<td>Yellow Iron Oxide FCF (Sicovit Gelb 10-BASF Cologne, Germany)</td><td>0.24% (or 0.25%)</td>

<td>Magnesium Stearate (USP grade, C. Erba, Milan, Italy)</td><td> 1,00%</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td> 0,40%</td>

<td>Together</td><td> 100,00%</td>

Glyceryl behenate and mannitol were mixed and the dye was carefully dispersed. The mixture was moistened with a 5% aqueous solution of polyvinylpyrrolidone. The mixture was passed through a 25-mesh screen, dried in an oven (dryer) at 30 ° C for about 2 hours, passed through a 25-mesh screen again, and dried to constant weight. Colloidal silica and magnesium stearate were added to the obtained granulate and mixed in a Turbula mixer for 15 minutes. In this way, a granulate (granulate 1 (b)) with good slip and good compressibility was obtained. The granulate was compressed as described below.

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1 (c) Manufacture of three-layer systems (by pressing).

Granules, obtained as previously described and in accordance with models known to those skilled in the art, were fed into feeders of a rotary press suitable for the production of three-layer tablets (e.g. Manesty Layer-Press LP 39, Liverpool, UK). In particular, the granules described in part 1 (b) were fed to the first and third feeders; while the granules as described in part 1 (a) were fed into the second feeder. The press was equipped with slightly concave round punches with a diameter of 9 mm.

The equipment was set up to produce three-layer systems consisting of a barrier of an initial amount of 130.0 mg of granules, a second layer (150 mg) containing the active ingredient (0.86 mg of ropinirole hydrochloride, corresponding to 0.75 mg of base) and a third barrier layer of 120 .0 mg of granules. Following the procedure described above, three-layer tablets with an average weight of 400.00 mg were obtained, each containing 0.86 mg of ropinirole hydrochloride corresponding to 0.75 mg of base. Table 4 shows the release pattern of the active ingredient from the tablets of Example 1.

Example 1A - variant of example 1

In a variant of Example 1, the granules for the active layer 1 (a) were prepared as follows.

HPMC, ropinirole, lactose, NaCMC, hydrogenated castor oil and maltodextrin were mixed for 6 minutes in a suitable mixer-granulator (Niro Fielder PMA type). The mixture was wetted with water (about 30% by weight of the products used). The obtained granulate was dried in a fluid bed dryer (Niro Fielder TSG 2 type) to a water content of 1 - 4.5% and then passed through a 1.57 mm screen in a conical mill. Silica was added and the mixture was mixed in a cubic mixer for 20 minutes, then magnesium stearate was added and mixed for a further 2 minutes.

In this variant, a granulate for the barrier layer 1 (b) was produced as follows.

Mannitol, dye, glyceryl behenate, HPMC and PVP were mixed for 6 minutes in a suitable mixer-granulator (Niro Fielder PMA type). The mixture was wetted with water (about 25% by weight of the products used). The obtained granulate was dried in a fluid bed dryer (Niro Fielder TSG 2 type) to a water content of 1.1 - 2.7% and then passed through a 1.57 mm screen in a conical mill. Silica was added and the mixture was mixed in a cubic mixer for 20 minutes, then magnesium stearate was added and the mixture was mixed for a further 2 minutes.

In a further variation, the above alternative procedures may also be used, mutatis mutandis, using the ingredients / formulations of any of Examples 2-11 below.

Example 2. Triple Layer Single Tablet Systems - 1.00 mg ropinirole

In Example 2, the first layer was a "barrier" layer (130 mg), the second layer (slow release) contained 1.14 mg of ropinirole hydrochloride corresponding to 1.00 mg of base; the third layer was the "barrier" layer (120 mg).

The granulate was prepared as described in Example 1 in Part 1 (a), with the only difference that the amount of active ingredient used was increased and the lactose content was reduced by the same amount; such granules form the second layer of the three-layer tablet.

2 (a) Preparation of the granulate used to form the slow release layer containing 1.14 mg of ropinirole hydrochloride corresponding to 1.00 mg of base.

<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 1.00 mg of base</td><td>1.14 mg</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 mg</td>

<td>Sodium Carboxymethyl Cellulose (Blanose 9 M31XF)</td><td>15.00 mg</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>47.46 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

PL 202 689 B1

A qualitatively and quantitatively identical granulate was used to form the first and third (barrier) layers as described in example 1 in section 1 (b). The press was equipped with slightly concave round punches with a diameter of 9 mm.

The device is set up to produce three-layer systems consisting of a barrier with an initial amount of 130.0 mg of granules, a second layer (150 mg) containing 1.14 mg of ropinirole hydrochloride (corresponding to 1.00 mg of ropinirole base) and a third barrier layer of 120 .0 mg of granules. Following the procedure described above, three-layer tablets with an average weight of 400.00 mg were obtained, each containing 1.14 mg of ropinirole hydrochloride, corresponding to 1.00 mg of base. Table 4 shows the release pattern of the active ingredient from the tablets of Example 2.

Example 3. Triple Layer Single Tablet Systems - 3.00 mg ropinirole

In Example 3, the first layer was the "barrier" layer (130 mg), the second layer (slow release) contained 3.42 mg of ropinirole hydrochloride corresponding to 3.00 mg of base; the third layer was the "barrier" layer (120 mg).

The granulate was prepared as described in Example 1 in Part 1 (a), with the only difference that the amount of active ingredient used was increased and the lactose content was reduced by the same amount; such granules formed the second layer of the three-layer tablet.

3 (a) Preparation of the granulate used to form the slow release layer containing 3.42 mg of ropinirole hydrochloride corresponding to 3.00 mg of base.

<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 3.00 mg of base</td><td>3.42 mg</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 mg</td>

<td>Sodium Carboxymethyl Cellulose (Blanose 9 M31XF)</td><td>15.00 mg</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>45.18 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

Qualitatively and quantitatively identical granules were used to form the first and third (barrier) layers as described in Example 1 in Part 1 (b). The press was equipped with slightly concave round punches with a diameter of 9 mm.

The equipment was set up to produce three-layer systems consisting of a barrier with an initial amount of 130.0 mg of granules, a second layer (150 mg) containing 3.42 mg of ropinirole hydrochloride (corresponding to 3.00 mg of ropinirole base) and a third barrier layer of 120 .0 mg of granules. By following the procedure described above, three-layer tablets with an average weight of 400.00 mg were obtained, each containing 3.42 mg of ropinirole hydrochloride corresponding to 3.00 mg of base. Table 4 shows the release behavior of the active ingredient from the tablets of Example 3.

Example 4. Single, triple layer tablet systems - 6.00 mg ropinirole

In Example 4, the first layer was the "barrier" layer (130 mg), the second layer (slow release) contained 6.84 mg of ropinirole hydrochloride corresponding to 6.00 mg of base; the third layer was the "barrier" layer (120 mg).

The granulate was prepared as described in Example 1 in Part 1 (a), with the only difference that the amount of active ingredient used was increased and the lactose content was reduced by the same amount; such granules form the second layer of the three-layer tablet.

4 (a) Preparation of granules used to form a slow release layer containing 6.84 mg of ropinirole hydrochloride corresponding to 6.00 mg of base

PL 202 689 B1

<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 6.00 mg of base</td><td>6.84 mg</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 mg</td>

<td>Sodium Carboxymethyl Cellulose (Blanose 9 M31XF)</td><td>15.00 mg</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>41.76 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

Qualitatively and quantitatively identical granules were used to form the first and third (barrier) layers as described in Example 1 in Part 1 (b). The press was equipped with slightly concave round punches with a diameter of 9 mm. The equipment was set up to produce three-layer systems consisting of a barrier of an initial amount of 130.0 mg of granules, a second layer (150 mg) containing 6.84 mg of ropinirole hydrochloride (corresponding to 6.00 mg of ropinirole base) and a third barrier layer of 120 .0 mg of granules. By following the procedure described above, three-layer tablets with an average weight of 400.00 mg were obtained, each containing 6.84 mg of ropinirole hydrochloride corresponding to 6.00 mg of base. Table 4 shows the release behavior of the active ingredient from the tablets of Example 4.

Example 5. Single Triple Layer Tablet Systems - 9.00 mg of ropinirole

In Example 5, the first layer was the "barrier" layer (130 mg), the second layer (slow release) contained 10.26 mg of ropinirole hydrochloride corresponding to 9.00 mg of base; the third layer was the "barrier" layer (120 mg).

The granulate was prepared as described in Example 1 in Part 1 (a), with the only difference that the amount of active ingredient used was increased and the lactose content was reduced by the same amount; such granules formed the second layer of the three-layer tablet.

5 (a) Preparation of granules used to form a slow release layer containing 10.26 mg of ropinirole hydrochloride corresponding to 9.00 mg of base

<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 9.00 mg of base</td><td>10.26 mg</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 mg</td>

<td>Sodium Carboxymethyl Cellulose (Blanose 9 M31XF)</td><td>15.00 mg</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>38.34 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

Qualitatively and quantitatively identical granules were used to form the first and third (barrier) layers as described in Example 1 in Part 1 (b). The press was equipped with round concave punches with a diameter of 8 mm. The equipment was set up to produce three-layer systems consisting of a barrier of an initial amount of 130.0 mg of pellets, a second layer (150 mg) containing the active ingredient (corresponding to 9.00 mg of ropinirole base) and a third layer of barrier18

PL 202 689 B1 with 120.0 mg of granules. Following the procedure described above, three-layer tablets having an average weight of 400.00 mg were obtained, each containing 9.00 mg of the active ingredient. Table 4 shows the release pattern of the active ingredient from the tablets of Example 5.

Example 6. Single Triple Layer Tablet Systems - 12.00 mg of ropinirole

In Example 6, the first layer was the "barrier" layer (130 mg), the second layer (slow release) contained 13.68 mg of ropinirole hydrochloride corresponding to 12.00 mg of base; the third layer was the "barrier" layer (120 mg).

The granulate was prepared as described in Example 1 in Part 1 (a), with the only difference that the amount of active ingredient used was increased and the lactose content was reduced by the same amount; such granules formed the second layer of the three-layer tablet.

6 (a) Preparation of the granulate used to form the slow release layer containing 13.68 mg of ropinirole hydrochloride, corresponding to 12.00 mg of base.

<td>Ingredient</td><td>Amount (mg)</td>

<td>Ropinirole hydrochloride equivalent to 12.00 mg of base</td><td>13.68 mg</td>

<td>Hydroxypropyl methylcellulose (Methocel® K 100 M, Colorcon, Orpington, UK)</td><td>61.50 mg</td>

<td>Sodium Carboxymethyl Cellulose (Blanose 9 M31XF)</td><td>15.00 mg</td>

<td>Maltodextrin NF (Lycatab DSH)</td><td>7.50 mg</td>

<td>Lactose (C. Erba, Milan, Italy)</td><td>34.92 mg</td>

<td>Hydrogenated castor oil (Cutina HR-Henkel, Germany)</td><td>15.00 mg</td>

<td>Magnesium stearate (C. Erba, Milan, Italy)</td><td>1.50 mg</td>

<td>Colloidal silica (Syloid 244, Grace GmbH, Worms, Germany)</td><td>0.90 mg</td>

<td>Together</td><td>150.00 mg</td>

Qualitatively and quantitatively identical granules were used to form the first and third (barrier) layers as described in Example 1 in Part 1 (b). The press was equipped with round concave punches with a diameter of 8 mm. The equipment was set up to produce three-layer systems consisting of a barrier with an initial amount of 130.0 mg of granules, a second layer (150 mg) containing the active ingredient (corresponding to 12.00 mg of ropinirole base) and a third barrier layer with 120.0 mg of granules. Following the procedure described above, three-layer tablets with an average weight of 400.00 mg were obtained, each containing a 12.00 mg of active ingredient. Table 4 shows the release pattern of the active ingredient from the tablets of Example 6.

Dissolution test of tablets prepared in examples 1-6

To evaluate the release characteristics of the active ingredient from the three-layer tablets discussed in Examples 1-6, a 2-blade equipment (USP XXIII) operating at 100 rpm was used with 500 ml of an aqueous citrate buffer solution (pH 4.0) as the dissolving fluid. ) at 37 ° C. The active ingredient release was then assessed by HPLC at 250 nm using an automatic sampling and reading system. The results of the conducted experiments are presented in Table 4.

Table 4

<td>Time (hours)</td><td colspan="6">Percentage released from tablets of Examples 1-6 (Ex. 1 - Ex. 6)</td>

<td></td><td>Ex. 1</td><td>Ex. 2</td><td>Ex. 3</td><td>Ex. 4</td><td>Ex. 5</td><td>Ex. 6</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td> 1</td><td> 7,3</td><td> 8,6</td><td> 7,8</td><td> 7,5</td><td> 8,8</td><td> 9,4</td>

<td> 2</td><td> 12,1</td><td> 12,6</td><td> 12,0</td><td> 13,4</td><td> 13,5</td><td> 14,0</td>

<td> 4</td><td> 18,9</td><td> 21,0</td><td> 19,5</td><td> 20,7</td><td> 22,1</td><td> 23,9</td>

PL 202 689 B1 cont. table 4

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td> 6</td><td> 26,0</td><td> 28,5</td><td> 27,9</td><td> 28,5</td><td> 29,8</td><td> 33,1</td>

<td> 9</td><td> 38,3</td><td> 39,7</td><td> 39,2</td><td> 40,3</td><td> 41,2</td><td> 44,9</td>

<td> 12</td><td> 49,6</td><td> 51,4</td><td> 50,7</td><td> 51,0</td><td> 52,6</td><td> 56,7</td>

<td> 16</td><td> 67,8</td><td> 66,9</td><td> 64,5</td><td> 66,3</td><td> 66,4</td><td> 70,0</td>

<td> 20</td><td> 82,0</td><td> 81,3</td><td> 78,4</td><td> 79,5</td><td> 80,3</td><td> 80,1</td>

<td> 24</td><td> 90,4</td><td> 91,3</td><td> 88,9</td><td> 89,1</td><td> 88,7</td><td> 91,2</td>

It can be indicated that the release of the drug from the manufactured systems is slowed down and the release of most of the drug takes approximately 24 hours.

Moreover, it is evident that the release kinetics are not substantially modified at any active ingredient content in the tablets. This behavior is in accordance with the invention.

Example 7. Preparation of Ropinirole Round Tablet Formulation

Ropinirole round tablet formulations were prepared as follows.

The tablet comprised an upper support or barrier layer 1, an active layer 2, and a lower support or barrier layer 3. HPMC is an abbreviation for Hydroxypropyl Methyl Cellulose.

Carrier layer (1)

<td>Ingredient</td><td>Function</td><td>Quantity (mg / tablet)</td>

<td>HPMC type 2208 / K 100M (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td> 58,18</td>

<td>Mannitol</td><td>Filler, thinner</td><td> 30,68</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 32,50</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 6,50</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,30</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,52</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,33</td>

<td>Purified water</td><td>Granulating liquid</td><td>b</td>

<td>Together</td><td></td><td> 130,00</td>

Active layer 2

It has been described for ropinirole tablet formulations containing 0.75 mg, 1 mg or 3 mg of ropinirole per tablet, based on the effective base.

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="3">Quantity (mg / tablet)</td>

<td>0.75 mg</td><td>1 mg</td><td>3 mg</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td>Ropinirole hydrochloride</td><td>The active substance</td><td> 0,855</td><td> 1,14</td><td> 3,42</td>

<td>Lactose Monohydrate</td><td>Filler, thinner</td><td> 47,745</td><td> 47,46</td><td> 45,18</td>

<td>HPMC type 2208 / K 100M (100,000 cP)</td><td>Hydrophobic matrix polymer</td><td>61.50 (41 wt.%)</td><td> 61,50</td><td> 61,50</td>

<td>Sodium carboxymethylcellulose</td><td>Viscosity regulating agent</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Maltodextrin</td><td>Binding agent</td><td> 7,50</td><td> 7,50</td><td> 7,50</td>

PL 202 689 B1 cont. table

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td>Hydrogenated castor oil</td><td>Hydrophobic compound</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,50</td><td> 1,50</td><td> 1,50</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,90</td><td> 0,90</td><td> 0,90</td>

<td>Purified water</td><td>Granulating liquid</td><td>b</td><td>b</td><td>b</td>

<td>Together</td><td></td><td> 150,00</td><td> 150,00</td><td> 150,00</td>

Carrier layer 3

<td>Ingredient</td><td>Function</td><td>Quantity (mg / tablet)</td>

<td>HPMC type 2208 / K 100M (100,000 cP)</td><td>Hydrophyte matrix polymer</td><td> 53,70</td>

<td>Mannitol</td><td>Filler, Thinner</td><td> 28,32</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 30,00</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 6,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,20</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,48</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,30</td>

<td>Purified water</td><td>Granulating liquid</td><td>b</td>

<td>Together</td><td></td><td> 120,00</td>

Purified water introduced as granulating liquid did not remain in the final product as indicated by the mark "b".

Example 8. Preparation of Ropinirole Caplet Formulations

Ropinirole caplet tablet formulations were prepared as follows. The tablet comprised an upper support or barrier layer 1, an active layer 2 and a lower support or barrier layer 3 as shown in Figure 9 (where the numerals 10, 12 represent barrier layers and 11 represent the active layer). HPMC is an abbreviation for Hydroxypropyl Methyl Cellulose. Four formulations of ropinirole tablets containing 1 mg, 3 mg, 6 mg, 9 mg or 12 mg of ropinirole per tablet, based on an effective base, have been described.

Carrier layer 1

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="4">Amount of ropinirole (mg / tablet)</td>

<td>1 mg</td><td>3 mg</td><td>6 or 9 mg</td><td>12 mg</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td> 76,07</td><td> 76,07</td><td> 76,07</td><td> 76,07</td>

<td>Mannitol</td><td>Filler, thinner</td><td> 40,12</td><td> 40,12</td><td> 40,12</td><td> 40,12</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 42,50</td><td> 42,50</td><td> 42,50</td><td> 42,50</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 8,50</td><td> 8,50</td><td> 8,50</td><td> 8,50</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,70</td><td> 1,70</td><td> 1,70</td><td> 1,70</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,68</td><td> 0,68</td><td> 0,68</td><td> 0,68</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,43</td><td> 0,43</td><td> 0,43</td><td> 0,43</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 170,00</td><td> 170,00</td><td> 170,00</td><td> 170,00</td>

PL 202 689 B1

Active layer 2

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="5">Amount of ropinirole (mg / tablet)</td>

<td>1 mg</td><td>3 mg</td><td>6 mg</td><td>9 mg</td><td>12 mg</td>

<td>Ropinirole hydrochloride</td><td>The active substance</td><td> 1,14</td><td> 3,42</td><td> 6,84</td><td> 10,26</td><td> 13,68</td>

<td>Monohydrate lactose</td><td>Filler, thinner</td><td> 47,46</td><td> 45,18</td><td> 41,76</td><td> 38,34</td><td> 34,92</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td>61.50 (41 wt.%)</td><td> 61,50</td><td> 61,50</td><td> 61,50</td><td> 61,50</td>

<td>Soda salt carboxymethyl cellulose</td><td>Viscosity regulating agent</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Maltodextrin</td><td>Binding agent</td><td> 7,50</td><td> 7,50</td><td> 7,50</td><td> 7,50</td><td> 7,50</td>

<td>Hydrogenated castor oil</td><td>Hydrophobic compound</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,50</td><td> 1,50</td><td> 1,50</td><td> 1,50</td><td> 1,50</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,90</td><td> 0,900</td><td> 0,90</td><td> 0,90</td><td> 0,90</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td><td>c</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 150,00</td><td> 150,00</td><td> 150,00</td><td> 150,00</td><td> 150,00</td>

Carrier layer (3)

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="4">Amount of ropinirole (mg / tablet)</td>

<td>1 mg</td><td>3 mg</td><td>6 or 9 mg</td><td>12 mg</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td> 62,65</td><td> 62,65</td><td> 62,65</td><td> 62,65</td>

<td>Mannitol</td><td>Filler, thinner</td><td> 33,04</td><td> 33,04</td><td> 33,04</td><td> 33,04</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 35,00</td><td> 35,00</td><td> 35,00</td><td> 35,00</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 7,00</td><td> 7,00</td><td> 7,00</td><td> 7,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,40</td><td> 1,40</td><td> 1,40</td><td> 1,40</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,56</td><td> 0,56</td><td> 0,56</td><td> 0,56</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,35</td><td> 0,35</td><td> 0,35</td><td> 0,35</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 140,00</td><td> 140,00</td><td> 140,00</td><td> 140,00</td>

Coating layer

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="4">Amount of ropinirole (mg / tablet)</td>

<td>1 mg</td><td>3 mg</td><td>6 or 9 mg</td><td>12 mg</td>

<td>FALLS OY-S-28876 WHITE</td><td>Coating agent</td><td> 13,80</td><td> 13,80</td><td> 13,80</td><td> 13,80</td>

<td>Purified water</td><td>Coating liquid</td><td>c</td><td>c</td><td>c</td><td>c</td>

<td>Total weight of the tablet (layers 1, 2, 3 and coating)</td><td></td><td> 473,80</td><td> 473,80</td><td> 473,80</td><td> 473,80</td>

Purified water introduced as granulating liquid or coating liquid did not remain in the final product as indicated by the "c" mark. The preparation OPADRY OY-S-28876 WHITE contained 63%

PL 202 689 B1

HPMC 2910 6 cP, 7% PEG 400, 30% TiO2. Red / pink (0.01-0.25%) and / or yellow (0.1 to 1.5%) coloring agents (iron oxides) may also be added, the amount of HPMC being 61-66%. The alternative blue coating contained 31-32% HPMC 2910 3 cP and HPMC 2910 5 cP, 8% PEG400, 23-24% TiO2, 1% polysorbate and 4-5% indigotine as the blue dye.

Example 9. Manufacture of ropinirole caplet formulation

Ropinirole caplet tablet formulations were prepared as follows. The tablet comprised an upper support or barrier layer 1, an active layer 2 and a lower support or barrier layer 3 as in Example 8. Four ropinirole tablet formulations containing 1 mg, 3 mg, 6 mg, 9 mg and 12 mg of ropinirole per tablet are described. , converted to the effective principle. This example was the same as example 8 but no yellow ferric oxide was used in the support or barrier layers.

Carrier layer 1

<td>Ingredient</td><td>Function</td><td>Amount of ropinirole (mg / tablet)</td>

<td></td><td></td><td>1, 3 or 6 mg</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td> 76,50</td>

<td>Mannitol</td><td>Filler, thinner</td><td> 40,12</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 42,50</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 8,50</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,70</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,68</td>

<td>Purified water</td><td>Granulating liquid</td><td>d</td>

<td>Together</td><td></td><td> 170,00</td>

Active layer 2

<td>Ingredient</td><td>Function</td><td colspan="5">Amount of ropinirole (mg / tablet)</td>

<td></td><td></td><td>1 mg</td><td>3 mg</td><td>6 mg</td><td>9 mg</td><td>12 mg</td>

<td>Ropinirole hydrochloride</td><td>The active substance</td><td> 1,14</td><td> 3,42</td><td> 6,84</td><td> 10,26</td><td> 13,68</td>

<td>Lactose Monohydrate</td><td>Filler, thinner</td><td> 47,46</td><td> 45,18</td><td> 41,76</td><td> 38,34</td><td> 34,92</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td>61.50 (41 wt.%)</td><td> 61,50</td><td> 61,50</td><td> 61,50</td><td> 61,50</td>

<td>Soda salt carboxymethyl cellulose</td><td>Viscosity regulating agent</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Maltodextrin</td><td>Binding agent</td><td> 7,50</td><td> 7,50</td><td> 7,50</td><td> 7,50</td><td> 7,50</td>

<td>Hydrogenated castor oil</td><td>Hydrophobic compound</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,50</td><td> 1,50</td><td> 1,50</td><td> 1,50</td><td> 1,50</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,90</td><td> 0,900</td><td> 0,90</td><td> 0,90</td><td> 0,90</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td><td>c</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 150,00</td><td> 150,00</td><td> 150,00</td><td> 150,00</td><td> 150,00</td>

PL 202 689 B1

Carrier layer 3

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td>Amount of ropinirole (mg / tablet)</td>

<td>1, 3 or 6 mg</td>

<td>HPMC type 2208 (100,000 cP)</td><td>Hydrophilic matrix polymer</td><td> 63,00</td>

<td>Mannitol</td><td>Filler, thinner</td><td> 33,04</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 35,00</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 7,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,40</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,56</td>

<td>Purified water</td><td>Granulating liquid</td><td>d</td>

<td>Together</td><td></td><td> 140,00</td>

Coating layer

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="4">Amount of ropinirole (mg / tablet)</td>

<td>1 mg</td><td>3 mg</td><td>6 or 9 mg</td><td>12 mg</td>

<td>FALLS OY-S-28876 WHITE</td><td>Coating agent</td><td> 13,80</td><td> 13,80</td><td> 13,80</td><td> 13,80</td>

<td>Purified water</td><td>Coating liquid</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td>Total weight of the tablet (layers 1, 2, 3 and coating)</td><td></td><td> 473,80</td><td> 473,80</td><td> 473,80</td><td> 473,80</td>

Purified water introduced as granulating liquid or coating liquid does not remain in the final product as indicated by the symbol "d".

Examples 10 and 11. Preparation of ropinirole caplet formulation

Ropinirole caplet tablet formulations were prepared as follows. The tablet comprised an upper support or barrier layer 1, an active layer 2, and a lower support or barrier layer 3 as in Examples 8 and 9. The formulations of Examples 10 and 11 are described as a single tablet containing 0.75 mg of ropinirole per tablet, based on effective base (0.855 mg in terms of the HCl salt). As can be seen, the formulations of Examples 10 and 11 have identical active layers to the active layer containing 0.75 mg of ropinirole in Example 7, but different barrier layers than Example 7, containing different amounts and grades of HPMC in the barrier layers, differing in replacement of mannitol. with lactose and less glyceryl behenate. As can be seen, Examples 10 and 11 used 10% and 40% by weight of K4M HPMC in the barrier layers, respectively, which gave a slightly faster in vitro release profile than about 45% by weight of K100M HPMC present in the barrier layers in Examples 1-6 and 7 - 9 as ropinirole migrates faster through the barrier layers, among others. Example 10 used 20 wt% K100LV HPMC as well as 10 wt% K4M HPMC in the barrier layer - Low Viscosity (LV) HPMC in the barrier layer can increase water uptake and aid gelling by increasing matrix viscosity and reducing release rate.

Support layer 1 for the formulations of Examples 10, 11

<td>Ingredient</td><td>Function</td><td colspan="2">Quantity (mg / tablet)</td>

<td></td><td></td><td>Example 10</td><td>Example 11</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>HPMC K 4M</td><td>Hydrophilic matrix polymer</td><td> 13,00</td><td> 51,84</td>

<td>HPMC K100LV</td><td>Hydrophilic matrix polymer</td><td> 26,00</td><td></td>

<td>Lactose Monohydrate</td><td></td><td> 64,68</td><td> 51,84</td>

PL 202 689 B1 cont. table

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 17,56</td><td> 17,55</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 6,50</td><td> 6,50</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,30</td><td> 1,30</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,64</td><td> 0,63</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,32</td><td> 0,32</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 130,00</td><td> 130,00</td>

Active layer 2 for the formulations of Examples 10 and 11

It has been reported for three ropinirole tablet formulations containing 0.75 mg of ropinirole per tablet, based on the effective base.

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td>Amount of ropinirole (mg / tablet)</td>

<td>0.75 mg</td>

<td>Ropinirole hydrochloride</td><td>The active substance</td><td> 0,855</td>

<td>Lactose Monohydrate</td><td>Filler, thinner</td><td> 47,745</td>

<td>HPMC type 2208 / K 100M (100,000 cP)</td><td>Hydrophobic matrix polymer</td><td> 61,50</td>

<td>Sodium carboxymethylcellulose</td><td>Viscosity regulating agent</td><td> 15,00</td>

<td>Maltodextrin</td><td>Binding agent</td><td> 7,50</td>

<td>Hydrogenated castor oil</td><td>Hydrophobic compound</td><td> 15,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,50</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,90</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td>

<td>Together</td><td></td><td> 150,00</td>

Carrier layer (3) for examples 10, 11

<td rowspan="2">Ingredient</td><td rowspan="2">Function</td><td colspan="2">Quantity (mg / tablet)</td>

<td>Example 10</td><td>Example 11</td>

<td>HPMC K4M</td><td>Hydrophilic matrix polymer</td><td> 12,00</td><td> 47,86</td>

<td>HPMC K100LV</td><td></td><td> 24,00</td><td></td>

<td>Lactose Monohydrate</td><td></td><td> 59,70</td><td> 47,86</td>

<td>Glyceryl behenate</td><td>Hydrophobic compound</td><td> 16,20</td><td> 16,20</td>

<td>Polyvinylpyrrolidone (Povidone)</td><td>Binding agent</td><td> 6,00</td><td> 6,00</td>

<td>Magnesium stearate</td><td>Lubricant</td><td> 1,20</td><td> 1,20</td>

<td>Colloidal silicon dioxide</td><td>Lubricant</td><td> 0,60</td><td> 0,60</td>

<td>Yellow ferric oxide</td><td>Coloring agent</td><td> 0,30</td><td> 0,30</td>

<td>Purified water</td><td>Granulating liquid</td><td>c</td><td>c</td>

<td>Together</td><td></td><td> 120,00</td><td> 120,00</td>

PL 202 689 B1

Purified water introduced as granulating liquid or coating liquid did not remain in the final product as indicated by the symbol "c".

Note: The active layer for each of the formulations of Examples 10 and 11 above may be replaced by the active layers of Examples 8 and 9 with 1 mg, 3 mg, 6 mg, 9 mg and 12 mg of ropinirole, based on the effective base.

Note: all examples with ropinirole 1-6 and 7-11 may use higher doses, up to 24 mg of ropinirole daily, e.g. 2 x 12 mg tablets. Other doses, e.g. 4 mg per day, may be administered using 1 x 1 mg and 1 x 3 mg tablets per day. Also, in any of Examples 1-6, other doses, e.g., 0.25 mg, 0.5 mg, and 2 mg of ropinirole may be used in the active layer by varying the amount of lactose and keeping the total weight of the active layer constant.

Example 12. Further studies of caplet preparation and drug dissolution profiles

Further studies on caplet manufacturing are presented to demonstrate the drug dissolution profiles for ropinirole caplets containing 0.75 mg, 6 mg or 12 mg of ropinirole on an effective base basis.

<td colspan="4">CR caplet formulation of ropinirole hydrochloride, details for layers, mg / tablet</td>

<td colspan="4">Ingredients</td>

<td colspan="4">Layer 1, carrying layer D14-4 yellow</td>

<td>HPMC type 2208 (100,000 cP)</td><td colspan="3"> 76,075</td>

<td>Mannitol</td><td colspan="3"> 40,120</td>

<td>Glyceryl behenate</td><td colspan="3"> 42,500</td>

<td>Povidone</td><td colspan="3"> 8,500</td>

<td>Yellow ferric oxide</td><td colspan="3"> 0,425</td>

<td>Vegetable Magnesium Stearate</td><td colspan="3"> 1,700</td>

<td>Colloidal silicon dioxide</td><td colspan="3"> 0,680</td>

<td>Purified water</td><td colspan="3">and</td>

<td>Together</td><td colspan="3"> 170,000</td>

<td>Layer 2, the active layer</td><td>0.75 mg</td><td>6 mg</td><td>12 mg</td>

<td>Ropinirole hydrochloride</td><td> 0,855</td><td> 6,840</td><td> 13,680</td>

<td>Lactose Monohydrate</td><td> 47,745</td><td> 41,760</td><td> 34,920</td>

<td>HPMC type 2208 (100,000 cP)</td><td> 61,500</td><td> 61,500</td><td> 61,500</td>

<td>Sodium carboxymethylcellulose</td><td> 15,000</td><td> 15,000</td><td> 15,000</td>

<td>Maltodextrin</td><td> 7,500</td><td> 7,500</td><td> 7,500</td>

<td>Hydrogenated castor oil</td><td> 15,000</td><td> 15,000</td><td> 15,000</td>

<td>Vegetable Magnesium Stearate</td><td> 1,500</td><td> 1,500</td><td> 1,500</td>

<td>Colloidal silicon dioxide</td><td> 0,900</td><td> 0,900</td><td> 0,900</td>

<td>Purified water</td><td>and</td><td>and</td><td>and</td>

<td>Total, layer 2</td><td> 150,000</td><td> 150,000</td><td> 150,000</td>

PL 202 689 B1 cont. table

<td colspan="2">Layer 3, carrying layer D14-4 yellow</td>

<td>HPMC type 2208 (100,000 cP)</td><td> 62,650</td>

<td>Mannitol</td><td> 33,040</td>

<td>Glyceryl behenate</td><td> 35,000</td>

<td>Povidone</td><td> 7,000</td>

<td>Yellow ferric oxide</td><td> 0,350</td>

<td>Vegetable Magnesium Stearate</td><td> 1,400</td>

<td>Colloidal silicon dioxide</td><td> 0,560</td>

<td>Purified water</td><td>and</td>

<td>Together</td><td> 140,000</td>

<td colspan="2">Coating with a layer</td>

<td>FALLS OY-S-28876 WHITE</td><td> 13,800</td>

<td>Purified water</td><td>and</td>

<td>Total, tablet</td><td> 473,800</td>

Notes: a = does not remain in the final product

0.855 mg of ropinirole hydrochloride corresponds to 0.75 mg of ropinirole as base 6.840 mg of ropinirole hydrochloride corresponding to 6.00 mg of ropinirole as base 13.680 mg of ropinirole hydrochloride corresponding to 12.00 mg of ropinirole base

Drug release profiles were determined using known methods. The results were as follows (results expressed as the percentage of drug released over a given time interval in hours):

<td colspan="7">Analytical results</td>

<td>Dosage, mg</td><td> 0,75</td><td> 0,75</td><td> 0,75</td><td> 6</td><td> 6</td><td> 6</td>

<td>Lot no</td><td>C511</td><td>C519</td><td>C529</td><td>C530</td><td>C531</td><td>C532</td>

<td>Pill</td><td>POOK41E</td><td>POOK40E</td><td>POOK39E</td><td>POOK45E</td><td>POOK46E</td><td>POOK47E</td>

<td>Tablet weight, mg</td><td> 471,95</td><td> 472,32</td><td> 472,08</td><td> 474,08</td><td> 471,50</td><td> 473,37</td>

<td>Relative standard deviation of the tablet weight,%</td><td> 0,78</td><td> 1,44</td><td> 0,65</td><td> 0,98</td><td> 1,10</td><td> 1,08</td>

<td colspan="7">Time, hours</td>

<td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td>

<td> 1,00</td><td> 8,96</td><td> 6,88</td><td> 7,43</td><td> 8,67</td><td> 8,20</td><td> 8,71</td>

<td> 2,00</td><td> 12,42</td><td> 11,45</td><td> 11,69</td><td> 13,47</td><td> 13,17</td><td> 13,48</td>

<td> 4,00</td><td> 19,99</td><td> 19,93</td><td> 19,59</td><td> 22,03</td><td> 22,01</td><td> 21,55</td>

<td> 6,00</td><td> 27,45</td><td> 27,62</td><td> 27,43</td><td> 30,21</td><td> 29,65</td><td> 30,17</td>

<td> 9,00</td><td> 38,24</td><td> 38,60</td><td> 38,34</td><td> 41,68</td><td> 41,46</td><td> 41,81</td>

<td> 12,00</td><td> 49,78</td><td> 49,58</td><td> 50,00</td><td> 52,07</td><td> 52,36</td><td> 52,33</td>

PL 202 689 B1 cont. table

<td> 16,00</td><td> 64,53</td><td> 64,48</td><td> 65,47</td><td> 66,17</td><td> 66,41</td><td> 66,26</td>

<td> 20,00</td><td> 77,17</td><td> 76,98</td><td> 78,68</td><td> 78,01</td><td> 78,34</td><td> 78,72</td>

<td> 24,00</td><td> 85,79</td><td> 86,17</td><td> 88,18</td><td> 87,09</td><td> 87,69</td><td> 88,19</td>

<td> 30,00</td><td> 92,40</td><td> 93,57</td><td> 95,40</td><td> 95,26</td><td> 94,81</td><td> 95,41</td>

<td> 36,00</td><td> 94,37</td><td> 96,00</td><td> 97,19</td><td> 97,96</td><td> 97,17</td><td> 97,58</td>

<td colspan="4">Analytical results</td>

<td>Dosage, mg</td><td> 12</td><td> 12</td><td> 12</td>

<td>Lot no</td><td>C512</td><td>C534</td><td>C535</td>

<td>Pill</td><td>POOK42E</td><td>POOK43E</td><td>POOK44E</td>

<td>Tablet weight, mg</td><td> 470,39</td><td> 473,62</td><td> 474,78</td>

<td>Relative standard deviation of the tablet weight,%</td><td> 0,93</td><td> 1,28</td><td> 1,02</td>

<td colspan="4">Time, hours</td>

<td> 0,00</td><td> 0,00</td><td> 0,00</td><td> 0,00</td>

<td> 1,00</td><td> 9,45</td><td> 10,10</td><td> 9,73</td>

<td> 2,00</td><td> 14,87</td><td> 15,53</td><td> 15,23</td>

<td> 4,00</td><td> 24,37</td><td> 24,87</td><td> 24,55</td>

<td> 6,00</td><td> 33,38</td><td> 33,74</td><td> 33,33</td>

<td> 9,00</td><td> 45,56</td><td> 46,22</td><td> 45,81</td>

<td> 12,00</td><td> 56,81</td><td> 57,40</td><td> 56,71</td>

<td> 16,00</td><td> 69,54</td><td> 70,90</td><td> 69,52</td>

<td> 20,00</td><td> 80,95</td><td> 81,64</td><td> 79,95</td>

<td> 24,00</td><td> 89,07</td><td> 89,76</td><td> 88,12</td>

<td> 30,00</td><td> 95,76</td><td> 96,63</td><td> 94,60</td>

<td> 36,00</td><td> 97,80</td><td> 99,38</td><td> 97,26</td>

Patent claims