Mazindol IR/SR multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (ADHD)

Abstract

The present invention relates to a modified-release composition of mazindol and its use in the treatment of attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness (i.e., incoercible sleepiness) or decline of vigilance (i.e., daytime somnolence) or excessive daytime sleepiness (e.g., narcolepsy, idiopathic hypersomnia) in particular in children, adolescents and adults.

Claims

1. A mazindol oral pharmaceutical unit dosage form in the form of a multilayer matrix-type tablet comprising: at least one immediate-release (IR) layer comprising mazindol and at least one diluent, at least one sustained-release (SR) layer comprising mazindol and at least one sustained-release, pH-independent and water-insoluble polymer, for a total amount of mazindol ranging from 1 to 6 mg and a ratio of mazindol in weight between the IR layers and the SR layers ranging from 40:60 to 80:20.

2. The unit dosage form according to claim 1, with a dissolution of between 60% and 80% at 1 hour, of between 70% and 90% at 2 hours, as measured according to the US Pharmacopeia Method 2 using a rotating blade method at 50 rpm in a 500 ml dissolution medium of 0.01 N HCl.

3. The unit dosage form according to claim 1, wherein the total weight of the unit dosage form ranges from 50 to 200 mg.

4. The unit dosage form according to claim 3, wherein the total weight of the unit dosage form is 100 mg.

5. The unit dosage form according to claim 1, wherein the diluent in said IR layers is selected in the group consisting of lactose, anhydrous lactose, spray-dried lactose, calcium carbonate, calcium sulfate, calcium sulfate dehydrate, calcium lactate trihydrate, monobasic calcium sulfate monohydrate, calcium carbonate, tribasic calcium phosphate, diabasic calcium phosphate, compressible sugars, dextrates, dextrin, dextrose, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, starch, modified starch, starch hydrolyzates, pregelatinized starch, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and sucrose.

6. The unit dosage form according to claim 1, wherein the sustained-release, pH-independent and water insoluble polymer is said SR layers is selected from the group consisting of cellulose polymers, high-molecular weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol (carbomers), polymers from the class of methacrylic acids, polyvinylalcohol derivatives, polymers of lactic and glycolic acids (PLGA), starches, waxes, polyvinyl acetate derivatives, polyvinylpyrrolidone derivatives and mixtures thereof.

7. The unit dosage form according to claim 1, further comprising a lubricant in each layer.

8. The unit dosage form according to claim 1, wherein said unit dosage form is capable of maintaining a steady-state mazindol plasma concentration in vivo at a reduced fluctuation above 40% of the Cmax(ss) value for at least 12 h.

9. The unit dosage form according to claim 8, wherein the reduced fluctuation is above 60% of the Cmax(ss) value.

10. The unit dosage form according to claim 1, for its use as medicinal product administered in repeat once-a-day form via oral route.

11. The unit dosage form according to claim 1, for use for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness or decline of vigilance or excessive daytime sleepiness.

12. The unit dosage form according to claim 11, for treating narcolepsy or idiopathic hypersomnia.

13. The unit dosage form according to claim 1, for use in combination with iron as a combination product for simultaneous, separate or sequential use.

14. The unit dosage form according to claim 11, for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness or decline of vigilance or excessive daytime sleepiness.

15. The unit dosage form according to claim 1, for use in combination with a psychostimulant as a combination product for simultaneous, separate or sequential use.

16. The unit dosage form according to claim 15, for treating attention deficit disorders (ADD) or attention deficit/hyperactivity disorder (ADHD) or related deficit of alertness or decline of vigilance or excessive daytime sleepiness.

17. The unit dosage form according to claim 1, wherein the weight ratio ranges from 50:50 to 70:30.

18. The unit dosage form according to claim 1, wherein the weight ratio is 50:50.

19. The unit dosage form according to claim 1, wherein the SR layer comprises a hydrophilic matrix.

20. A process for preparing the unit dosage form according to claim 1, comprising: (a) preparing the blend of the excipients of the IR layers, (a′) preparing the blend of the excipients of the SR layers, (b) adding the IR blend of step (a) and the SR blend of step (a′) into a multilayer tablet press.

21. The process according to claim 20, wherein the multilayer tablet press is a bilayer tablet press.

Description

FIGURES

(1) FIGS. 1-6 depict dissolution profiles of the prototype tablets of Example 3.

(2) FIG. 1: Overlay of All Dissolution Profiles

(3) FIG. 2: Overlay of Series 1 Formulations

(4) FIG. 3: Overlay of Series 2 Formulations

(5) FIG. 4: Overlay of Dissolution Profiles for 50/50 IR/SR Ratio Tablet Formulations

(6) FIG. 5: Overlay of Dissolution Profiles for 60/40 IR/SR Ratio Tablet Formulations

(7) FIG. 6: Overlay of Dissolution Profiles for 70/30 IR/SR Ratio Tablet Formulations

(8) FIG. 7: Overlay of Dissolution Profiles from Batch 100-15021 Tablets Analyzed Using UV Probes (100-15021) and HPLC Analysis (15021LC)

(9) FIG. 8: Overlay of Dissolution Profiles from Batch 100-15022 Tablets Analyzed Using UV Probes (100-15022) and HPLC Analysis (15022LC)

DETAILED DESCRIPTION

(10) The pharmaceutical composition according to the present invention is a mazindol oral pharmaceutical unit dosage form in the form of a multilayer matrix-type tablet comprising: at least one immediate-release (IR) layer comprising mazindol and at least one diluent, at least one sustained-release (SR) layer comprising mazindol and at least one sustained-release, pH-independent and water-insoluble polymer,
for a total amount of mazindol comprised between 1 and 5 mg and a ratio in weight between the IR layers and the SR layers comprised between 40:60 and 80:20 preferably between 50:50 and 70:30, more preferably of 50:50. Preferably, the unit dosage form according to the invention is a bilayer tablet.

(11) In an embodiment of formulation of the invention, the dissolution of mazindol can be between 60% and 80% at 1 hour and between 70% and 90% at 2 hours, as measured in accordance with the rotating blade method at 50 rpm according to the US Pharmacopeia Method 2, in a dissolution medium 0.01N HCl, 500 mL. In another embodiment, a unit dosage form according to the invention can have a dissolution of 50%-65% at 0.5 hours, 55%-85% at 1 hour, 65%-95% at 2 hours, not less than 75% at 4 hours, and not less than 85% at 8 hours.

(12) Preferably, the unit dosage form according to the invention is of between 50 and 200 mg, preferably of 100 mg. Preferably, the unit dosage form according to the invention comprises between 2 and 5 mg of mazindol, preferably of between 1 and 3 mg, more preferably of 4 mg.

(13) Preferably, the unit dosage form according to the invention maintains the steady-state mazindol plasma concentrations obtained in vivo with a reduced fluctuation of above 40% of the Cmax(ss) value, preferably above 50% of the Cmax(ss) value, and preferably above 60% of the Cmax(ss) for at least 12 h.

(14) Examples of diluents include: lactose, monohydrate lactose, anhydrous lactose, spray-dried lactose, calcium carbonate, calcium sulfate, calcium sulfate dehydrate, calcium lactate trihydrate, monobasic calcium sulfate monohydrate, calcium carbonate, tribasic calcium phosphate, diabasic calcium phosphate, compressible sugars, dextrates, dextrin, dextrose, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, starch, modified starch, starch hydrolyzates, pregelatinized starch, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and sucrose, preferably lactose, anhydrous lactose, spray-dried lactose, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives.

(15) Diluent concentration in the IR layers can be varied between 1 and 95%, preferably 30 and 60%, more preferably 45 to 55% by weight of the total weight of the IR layers.

(16) Preferably, a unit dosage form according to the invention comprises a lubricant in each layer.

(17) Lubricants and glidants can be employed in the present application to prevent, reduce or inhibit adhesion or friction of ingredients of the composition. They facilitate the compression and ejection of compressed compositions from a desired die. They are compatible with the ingredients of the pharmaceutical composition, and they do not significantly reduce the solubility, hardness, chemical stability, physical stability, or the biological activity of the pharmaceutical composition. The pharmaceutically acceptable lubricants and glidants for the present application are selected from the group including but not limited to stearic acid, metallic stearates, zinc stearate, magnesium stearate, magnesium trisilicate, calcium hydroxide, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium stearate, glyceryl monostearate, waxes, glycerides, glyceryl behenate, glyceryl palmitostearate, silicone oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, mineral oil, polyethylene glycol, methoxypolyethylene glycol, sodium acetate, sodium oleate, sodium chloride, leucine, sodium benzoate, alkyl sulfates, sodium lauryl sulfate, sodium stearyl fumarate, talc, colloidal silica, corn starch, powdered cellulose, and/or boric acid. The preferred range of lubricants/glidants is from 0% to 1% w/w of the layer.

(18) The sustained-release, pH-independent and water-insoluble polymer in SR layers of the tablets according to the invention is selected in the group consisting of cellulose polymers, high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol (Carbopol, Carbomers), polymers from the class of methacrylic acids, polyvinylalcohol derivatives, polymers of lactic and glycolic acids (PLGA), starches, waxes, polyvinyl acetate derivatives, polyvinyl pyrrolidone derivatives and mixtures thereof, preferably is selected in the group consisting of cellulose polymers and high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol (Carbopol, Carbomers).

(19) Cellulose polymers include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium CMC, ethyl cellulose derivatives such as cellulose acetate, cellulose acetate butyrate, cellulose acetate cellulose propionate, hydroxypropylmethylcellulose acetate succinate, microcrystalline cellulose (for example such as the one supplied under the trade mark Avicel®, and ethylcellulose (for example the one supplied under the trade mark Aqualon® ethylcellulose).

(20) Polymers from the class of methacrylic acids include the grades Eudragit®RL 12.5, RL PO and RL 100 and RS 12.5, RS PO and RS 100. Starches include natural starches e.g. corn starches and modified starches such as pre-gelled starch. Waxes include white or yellow beeswax, polyvinyl acetate derivatives.

(21) Sustained-release, pH-independent and water-insoluble polymer concentration in the SR layers can be varied between 80 and 99%, preferably 90 to 97% by weight of the total weight of the SR layers.

(22) The unit dosage form according to the invention can include anti-agglomerant agents. anti-agglomerant agents used in the present invention include talc, silicon dioxide and its derivatives, acrylic esters, castor oil derivative, cellulose compounds, iron oxides, magnesium stearate, stearic acid and or sodium stearate.

(23) Layers of the tablet according to the present invention can comprise a binder. Binders according to the invention, include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), maltodextrin, polyvinylpyrrolidone (PVP) and or microcrystalline cellulose.

(24) The compression matrix can advantageously include, additionally to the excipients of the compression matrix, one or more excipients intended either to promote the proper conducting of the compression process.

(25) A metabolite of mazindol, referred to as 2-(2-aminoethyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidine or 2-(p-Chlorobenzoyl)-N-2-(aminoethyl)benzamide), has a Cmax that is approximately ¼ that of mazindol and a half-life that is longer than mazindol. It may accumulate and contribute to the efficacy of mazindol, particularly at steady-state. A dose of 0.25 mg to 12 mg of this metabolite may be used in the treatment of narcolepsy or ADHD.

(26) The invention also relates to a process for preparing the unit dosage form according to the invention, comprising the following steps: (a) preparing the blend of the excipients of the IR layers, (a′) preparing the blend of the excipients of the SR layers, (b) adding the IR blend of step (a) and the SR blend of step (a′) into a multilayer, preferably a bilayer, tablet press.

(27) Mazindol undergoes hydrolysis at moderate temperatures with minimal amount of water. Elimination of water in a mazindol formulation therefore provides better stability. In preparing a unit dosage of the invention, preferably no water is added to the process. In one aspect of this invention, a mazindol formulation is provided that is substantially free of water, such that the amount of water by weight is less than 1.5%, 1%, or preferably less than 0.5%. Because the preferred process for formulating the bilayer or multilayer tablets of the present invention does not use water, it effectively eliminates moisture and consequently provides better stability to the bilayer or multilayer tableted formulations of the present invention. Moreover, the bilayer or multilayer design of the present invention provides better homogeneity and less variation in tablet uniformity to deliver consistency in the amount of the mazindol in the tablet and ultimately administered.

(28) In the context of the present invention, the diagnosis of attention-deficit/hyperactivity disorder (ADHD) is based on the clinical characteristics defined by the international classification used by ICD-10 (International Classification of Diseases (ICD). World Health Organization) and DSM-V (Diagnostic and Statistical Manual of Mental Disorders, 5.sup.th edition).

(29) The criteria of DSM-V includes three dimensions (inattention, impulsivity and hyperactivity), normal intellectual efficiency (IQ>80) and having isolated iron deficiency, but not anaemic, that is to say having a normal haemoglobin level. The expression “iron deficiency” means hypoferrinaemia without significant modification to the serum concentration of soluble transferrin receptors.

(30) “ADHD symptom” designates in particular attention disorders such as inattention, impulsivity, impatience, oppositional disorders, but also daytime or night-time motor hyperactivity, restless legs syndrome, and insomnia.

(31) Insomnia designates: a. onset insomnia that is characterised by difficulties in falling asleep; b. maintenance insomnia that is characterised by night-time motor hyperactivity and waking up during the night, and c. psychopathological insomnia, generally chronic and generally linked to anxiety, stress and depressive episodes.

(32) The criteria for evaluating the efficacy of the treatment of attention-deficit/hyperactivity disorder by of the modified-release pharmaceutical composition comprising mazindol optionally in association with iron and/or a psychostimulant in the treatment of attention-deficit/hyperactivity disorder according to the present invention are the reduction (>30%) in the rating scale severity score for attention-deficit/hyperactivity symptoms AHD-RS (after 12 weeks of treatment, and an improvement in severity scores for Conner's Parent questionnaire (CPRS), Conner's Teacher questionnaire (CTRS) and CGI (clinical global impressions). Subjective somnolence is assessed using the CASS scale (child and adolescent somnolence scale). The quality of falling asleep is assessed by means of the restless legs syndrome severity scale.

(33) The patient according to the invention is chosen from among a newborn baby, a child, an adolescent and an adult. According to a preferred embodiment, the patient is a child or an adolescent or an adult, even more preferably a child aged approximately 5 to 12 years. The patient according to the invention advantageously suffers iron deficiency, but is not anaemic. Ferritin deficiency can be measured in the serum, but also in all other biological fluids such as the cerebrospinal fluid.

(34) A ferritin deficiency corresponds to a serum concentration of ferritin in the adult patient of less than approximately 50 μg/litre. This deficit of iron storage” (expressed by a low ferritin level) may reach ferritin concentrations of less than approximately 40 μg/l, or even less than approximately 35 μg/l, less than 30 μg/l, less than 20 μg/l, less than 15 μg/l, or even less than approximately 10 μg/l. The techniques of determining serum ferritin are well known to persons skilled in the art. The immunoenzymatic method (IMX ferritin kit, Abbot Laboratories) can be cited.

(35) The patient according to the invention also has a normal serum concentration of receptors soluble to transferrin. Transferrin is involved in the acquisition of iron by the cells of the organism; this acquisition is controlled by the number of transferrin receptors existing on the cell surface. The concentration of these receptors can be evaluated by techniques known to persons skilled in the art such as nephelemetry (Ruivard et al. 2000 Rev Méd Interne 21: 837-843). A normal range of concentration of receptors soluble to transferrin is 2.0-4.50 mg/l for men and 1.80-4.70 mg/l for women (see RsTF kit Ref 2148315 from Roche).

(36) According to another aspect of the present invention, mazindol is used in combination with iron as a combination product for simultaneous, separate or sequential use.

(37) According to a preferred method of use, the iron is used as a supplement with the patient before the administration of mazindol. Within the meaning of the present invention, “iron” means iron in the form of an iron atom, iron salt or organic iron, or any formulation containing iron that is pharmaceutically acceptable. By way of a non-exhaustive list, the pharmaceutically acceptable iron salt is selected from ferrous salts and ferric salts, preferably from ferric ammonium citrate, ferric pyrophosphate, ferrocholinate, ferrous abscorbate, ferrous aspartate, ferrous chloride, ferrous sulphate, ferrous tartrate, ferrous fumarate, ferrous gluconate, ferrous gluceptate, ferrous sulphate glycine, ferrous lactate, ferrous oxalate and ferrous succinate.

(38) According to a preferred embodiment of the invention, the iron salt is ferrous sulphate, and preferably gastro-protected ferrous sulphate.

(39) Alternatively, the pharmaceutical acceptable iron is in the form of dextran iron, sucrose iron, poly-maltose iron, or sorbitol iron. When the iron is in the form of pharmaceutically acceptable organic iron, it is preferably iron biglycinate, iron glycinate or iron protein succinylate.

(40) According to a preferred embodiment, the use of mazindol possibly in association with the iron according to the invention is implemented in combination with at least one compound selected from psychostimulants, as a combination product for simultaneous, separate or sequential use.

(41) Psychostimulant compounds designate dopamine and/or noradrenaline uptake inhibitors and agonists of catecholamines. Among these, the following can be cited non-exhaustively:

(42) 1) psychostimulant compounds: methylphenidate (speciality Ritalin®, Concerta®, Equasym®, Quasym, Medikinet Retard®), armodafinil (Nuvigil®), modafinil (Sparlon®, Modiodal®, Provigil®), atomoxetine (Strattera®), bupriopion, and amphetamines such as d-amphetamine, dexedrine, dexamphetamine and lisdexamfetamine (Vyvanse®, Elvanse®).

(43) 2) L-Dopa: Modopar, Sinemat

(44) 3) selective dopamine agonists: pramipexole (Sifrol®, Mirapex®), ropinirole (Requip®, Adartrel®), lisuride, pergolide, cabergoline, etc.

(45) In particular, when mazindol is used in association with ferrous sulphate, the quantity of ferrous sulphate administered to the patient on a daily basis is between 0.1 mg and 10 mg, preferably between 100 mg and 2 g per day, preferably approximately 500 mg, in one or more doses.

(46) More particularly, according to the present invention, the patients undergo iron supplementation, in particular ferrous sulphate, for 12 weeks and the treatment with mazindol for 12 weeks.

(47) According to the present invention, the composition may also comprise iron or one of its pharmaceutically acceptable salts and/or a psychostimulant.

(48) In an embodiment of the invention, a controlled release formulation of mazindol is provided containing immediate and sustained release layers in a layered tablet, which when ingested leads to an initial burst of mazindol followed by a slower, continual release, for example, over 6-8 hours (from ingestion) where it can be dissolved and absorbed in the small intestine, before it reaches the colon. The initial availability of mazindol is advantageous for ADHD patients because they need a sufficient level of mental alertness and acuity at the beginning of their day so that they can concentrate, for instance, on work or driving to work. Subsequently, the slower continual release and absorption of mazindol in the intestine provided by the formulation of the present invention assures that adequate plasma concentrations are achieved throughout the day and evening (e.g., for completion of the workday or homework), while allowing the subject to fall asleep and remain asleep during the night.

(49) Data using the in vitro TIM gastrointestinal system (a dynamic, multi-compartmental system simulating the human stomach and small intestines for studying the behavior of oral dosage strengths under various physiological gastrointestinal conditions) showed that the amount of mazindol that is bioaccessable, when formulated according to the present invention, is similar under fasted and fed conditions; however, the Tmax in the fed state is delayed, compared to the fasted state, by one hour or more, suggesting a food effect for mazindol. If a rapid onset is sought, one would expect from these data that a patient may have to wait about 2 hours after administration of mazindol before having breakfast. Advantageously, however, using the formulation of the present invention in vivo, mazindol can be taken at significantly less time before consuming a meal (e.g., 30 minutes) and still obtain an initial high release of mazindol in the stomach while not having to unnecessarily delay eating yet have a Tmax in the fed state that is not later than in the fasted state. As discussed, this is particularly beneficial for ADHD patients, for this initial amount of mazindol provided increases patients' mental alertness and acuity at the start of their day (e.g., driving to work, starting school).

(50) Konofal (2014) reported that there was no relationship between Cmax of mazindol and efficacy or safety in children with ADHD. Unexpectedly, a lower Cmax after administration of a mazindol formulation of the present invention can lead, without compromising efficacy, to a muted increase in the heart rate compared to administration of, for example, an immediate release formulation of mazindol. If the Cmax after administration of a formulation of the present invention is 20% to 40% lower than the Cmax after administering an immediate release formulation of mazindol, the increase in heart rate associated with mazindol administration could surprisingly and unexpectedly be 4 to 11 beats/min less with the formulation of the present invention. This is a clinically relevant and significant outcome.

EXAMPLES

Example 1: Conditions for the Dissolution Profiles

(51) Dissolution Medium: 0.01N HCl

(52) Medium Volume: 500 mL

(53) USP Apparatus 2 (Paddles)

(54) Speed: 50 rpm

(55) Medium Temperature: 37° C.±0.5° C.

(56) Test 6 tablets (unless otherwise specified)

(57) Timepoints: 1, 2, 4, 6, and 8 hours

(58) Sample approximately 5 mL from each vessel using a syringe or autosampler with cannulae and a 10 μm full flow filter attached.

Example 2: Process for Manufacture of Mazindol Bilayer Tablets

(59) A, Manufacturing process for the sustained release (SR) layer (2 mg. tablet)

(60) 1. Weigh the following ingredients: concentration w/w %

(61) TABLE-US-00001 a. Mazindol 2.0 b. Lactose monohydrate NF/hypromellose NF (Retalac ®) 97.0 c. Carbopol 971P 0.5 d. Magnesium stearate 0.5 Total = 100%

(62) 2. Screen ingredients a, b, c, from step 1 into the V blender and blend for 20 minutes.

(63) 3. Pass the ingredients from Step 2 through the Comil.

(64) 4. Add the ingredients from Step 3 into the V blender.

(65) 5. Screen item d from Step 1 into the blender and blend for 5 minutes,

(66) 6. Collect material from Step 5 for tablet manufacture.

(67) B. Manufacturing process for the immediate release (IR) layer (2 mg) tablet:

(68) 1. Weigh the following ingredients: concentration w/w %

(69) TABLE-US-00002 a. Mazindol 2.0 b, Lactose monohydrate, NF 97.5 c. Magnesium stearate 0.5 Total = 100%

(70) 2. Screen ingredients a, b, from Step 1 into the V blender and blend for 20 minutes

(71) 3. Pass ingredients from Step 2 through the Comil

(72) 4. Add ingredients from Step 3 into the V blender.

(73) 5. Screen item c from Step 1 into the blender and blend for 5 minutes.

(74) 6. Collect material from Step 5 for tablet manufacture.

(75) C. Tablet manufacture: 1. Set bilayer press for correct weight. 2. Add the IR blend to hopper 1. 3. Add the SR blend to hopper 2. 4. Compress tablets to a total weight of 100 mg.

Example 3: Dissolution Profiles of the Bilayer Tablets of Example 2

(76) 6 bilayer tablets have been prepared. Dissolution was performed per USP monograph for Mazindol tablets.

(77) Data was collected using Pion Rainbow UV probes on n=3 tablets per batch. % Release values are reported as the average of either two or three tablets per prototype batch.

(78) The bilayer tablet formulations are based on two sustained release (SR) formulations and one immediate release (IR) formulation.

(79) The IR formulation is combined at three mass/mass ratios (IR/SR=50/50, 60/40, & 70/30) with each SR formulation to create 6 bilayer tablet prototypes.

(80) The quantitative formulations for each of the prototype tablets are given in tables 1 and 2 along with their R&D batch number designation.

(81) Table-1 formulations include the SR formulation which utilizes HPMC and Carbopol 971P to modulate Mazindol dissolution and are categorized as Series 1 prototype formulations.

(82) Table-2 formulations include the SR formulation which incorporates two different molecular weight grades of HPMC to modulate Mazindol dissolution and are categorized as Series 2 prototype formulations.

(83) Table-3 reports the dissolution testing results for each of the prototype formulations.

(84) TABLE-US-00003 TABLE 1 Series 1 Prototype Tablet Formulations Batch Number 100-15018 100-15019 100-15020 IR layer/SR layer Ratio 50/50 60/40 70/30 Ingredients mg/Tablet mg/Tablet mg/Tablet IR Layer Formulation Mazindol 0.5 0.6 0.7 Lactose Monohydrate 49.25 59.1 68.95 Magnesium Stearate 0.25 0.3 0.35 SR Layer Formulation Mazindol 0.5 0.4 0.3 Lactose/HPMC K4M (Retalac ®) 49 39.2 29.4 Carbopol 971P 0.25 0.2 0.15 Magnesium Stearate 0.25 0.2 0.15

(85) TABLE-US-00004 TABLE 2 Series 2 Prototype Tablet Formulations Batch Number 100-15021 100-15022 100-15023 IR layer/SR layer Ratio 50/50 60/40 70/30 Ingredients mg/Tablet mg/Tablet mg/Tablet IR Layer Formulation Mazindol 0.5 0.6 0.7 Lactose Monohydrate 49.25 59.1 68.95 Magnesium Stearate 0.25 0.3 0.35 SR Layer Formulation Mazindol 0.5 0.4 0.3 Lactose/HPMC K4M (Retalac ®) 36.75 29.4 22.05 HPMC K100M 12.5 10 7.5 Magnesium Stearate 0.25 0.2 0.15

(86) TABLE-US-00005 TABLE 3 Dissolution Results for Prototype Tablet Batches (UV Probe Analysis Data) Batch # 100- 100- 100- 100- 100- 100- 15018 15019 15020 15021 15022 15023 Formulation Series 1 Series 2 IR/SR Ratio 50/50 60/40 70/30 50/50 60/40 70/30 Time % Re- % Re- % Re- % Re- % Re- % Re- (Hours) leased leased leased leased leased leased 0.5 60.07% 63.29% 75.33% 64.81% 69.79% 71.62% 1 69.01% 76.04% 87.15% 73.78% 78.84% 80.63% 1.5 74.97% 80.03% 89.50% 80.00% 83.40% 83.91% 2 80.47% 84.20% 91.17% 84.32% 86.23% 86.29% 3 86.31% 89.64% 95.69% 91.21% 91.58% 91.63% 4 90.87% 92.71% 96.48% 94.11% 94.52% 94.44% 5 93.57% 94.78% 97.19% 96.40% 95.85% 95.21% 6 95.47% 96.13% 97.49% 98.03% 97.09% 96.81% 7 96.48% 97.27% 99.30% 98.58% 97.92% 97.72% 8 97.92% 98.80% 99.45% 99.06% 98.50% 99.39% 9 98.57% 99.61% 98.84% 99.91% 98.77% 98.94% 10 99.87% 99.44% 99.65% 99.77% 99.36% 100.00%

(87) All prototype tablet batches were tested in two distinct dissolution runs, one n=3 run analyzed using the UV probes and one n=4 run using HPLC analysis.

(88) Table-4 reports the results for the n=3, UV analyzed dissolution testing compared to the n=4, HPLC analyzed dissolution testing for batches 100-15021 and 100-15022.

(89) TABLE-US-00006 TABLE 4 UV Probe Analysis vs. HPLC Analysis of Dissolution Samples Batch # 100-15021 100-15022 Quantitation UV Probe HPLC UV Probe HPLC Time (hours) % Released % Released % Released % Released 1 73.78% 73.0% 78.84% 73.4% 2 84.32% 87.6% 86.23% 88.5% 4 94.11% 95.8% 94.52% 94.5% 6 98.03% 98.0% 97.09% 96.3%

(90) The dissolution data for the prototype tablets reveal the Series 1 formulations to have the greatest differentiation among the dissolution profiles at the early time points.

(91) The Series 2 formulations display a slighter differentiation at these time points for the range of SR/IR layer weight ratios.

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