Pharmaceutical matrices for prolonged drug release

Abstract

The present invention relates to a mixture of excipients for the controlled release of an active ingredient, in particular trazodone, which confers controlled release properties to the drug in the 24 hours following oral administration. The tablet comprising such a mixture of excipients may also be prepared simply by mixing all the excipients and the active ingredient together.

Description

[0001] “Pharmaceutical matrices for prolonged drug release’

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to controlled release pharmaceutical formulations for the administration of drugs dosable once a day and produceable by mixing and direct compression.

[0004] BACKGROUND ART

[0005] Trazodone, or 2-[3-[4-(3-chlorophenyl)-1 -piperazinylpropyl]-1 ,2,4- triazole[4,3-a]pyridin-3(2H)-one, is a multifunctional and multimodal antidepressant drug which acts by means of 5-HT receptors and inhibits the 5-HT carrier.

[0006] Trazodone is classified as a "multimodal" antidepressant (Sulcova A., Psichiatria, 2015, 19 (1 ), 49-52), with a resulting pharmacological profile which is distinct from that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).

[0007] Since its introduction in the 1970s, trazodone has proven its antidepressant equivalence to other known antidepressants belonging to different classes, such as tricyclics (Bryant SG et al., Journal of Clinical Psychiatry, 1990, 51 , 27-29), SSRIs, including fluoxetine (Beasley C. M. et al., Journal of Clinical Psychiatry, 1991 , 52, 294-299), paroxetine (Kasper S. et al., Current Medical Research and Opinion, 2005, 21 (8), 1139-1146), sertraline (Munizza C. et al., Current Medical Research and Opinion, 2006, 22 (6), 1703-1713) and SNRIs, such as venlafaxine (Cunningham L.A. et al., Journal of Clinical Psychopharmacology, 1994, 14 (2), 99-106).

[0008] Trazodone is currently produced in free base form and as a pharmaceutically acceptable acid addition salt, both of which described below. The preferred form for administration is the hydrochloride salt obtained by treatment of the free base with hydrochloric acid.

[0009] TRAZODONE BASE TRAZODONE HYDROCHLORIDE

[0010] The preparation of trazodone was first described in US Patent 3,381 ,009. Since then, several pharmaceutical forms have been developed, also for OAD (Once A Day) administration, such as those described in EP1931346B1 , based on the use of Contramid®.

[0011] The development of pharmaceutical forms for oral administration, in particular those with controlled release, requires a thorough knowledge of the chemical-physical features of the drug, on which the release and absorption thereof in the gastrointestinal (Gl) tract depend.

[0012] The solubility of trazodone is pH dependent; in fact, trazodone has a pKa of 6.74 in water and is therefore highly soluble in an acidic environment where the pH is lower than the pKa thereof, for example in the stomach and upper intestine (duodenum), while it is poorly soluble in the lower gastrointestinal tract (colon) where the pH is higher than the pKa thereof. This complicates the development of slow-release pharmaceutical forms (for example, over 8 hours), which require constant solubility and absorption along the whole gastrointestinal tract throughout the 24 hours for a better adherence to treatment should a Once A Day administration be used.

[0013] The Once A Day (OAD) trazodone tablets described in EP 1931346 B1 constantly release trazodone within 1 hour of the administration thereof up to over 24 hours thereafter. In these formulations, the release of trazodone is not pH dependent and it is therefore uniform in the upper gastrointestinal tract with a lower pH, as in the lower one, which has a higher pH. This release allows for a substantially constant absorption starting from about one hour after the drug intake.

[0014] The result has been made possible by virtue of the properties of Contramid®, a cross-linked starch with a high amylose content, the preparation of which requires as a starting reagent a starch with a high amylose content (at least 70%) (the average amylose content of the most common starches is about 40%) which is cross-linked (e.g., with epichlorohydrin, adipic acid anhydride, sodium trimetasulfate and phosphorus oxychloride) in a very basic environment and chemically modified, e.g., by hydroxypropylation and subsequently gelatinized. The preparation of Contramid® is described in EP1305009 B1.

[0015] EP 1931346 B1 patent also describes the process for preparing OAD (Once A Day) formulations with Contramid®, which is not particularly complex.

[0016] The present invention, relating to a formulation with a constant and controlled release of trazodone starting from about 1 hour after the administration thereof, up to the following 24 hours, responds to the needs to identify alternative formulations which may be administered once a day, and the preparation of which is equally simple. The present invention allowed to further simplify the preparation of OAD tablets, allowing the replacement of Contramid® with a fully pre-gelatinized noncustomized starch, simple to prepare and easily available on the market.

[0017] DESCRIPTION OF THE FIGURES

[0018] Figure 1. Release profile of reference compositions of trazodone HCI OAD 150 mg (Panel A) and 300 mg (Panel B), prepared according to Examples 1 and 3 of EP1931346 B1 , and described in Example 1 - Experimental Part). Diss. %: dissolution percentage.

[0019] Figure 2. Release profiles of compositions of trazodone 150 mg, in which Contramid® was replaced with the same amount of partially pregelatinized starch (Starch 1500, Panel A, as described in Example 2 (Test 1 ); or, Panel B, with the larger amount (350 mg) as described in Example 2, Test 3. Each profile was compared to the release profile of the reference composition. Diss. %: dissolution percentage.

[0020] Figure 3. Release profiles of compositions of trazodone 150 mg, in which Contramid® was replaced with the same amount of microcrystalline cellulose (Panel A), as described in Example 3, Test 4, or with 350 mg of fully pre-gelatinized starch (Panel B), as described in Example 3, Test 5. Each profile is compared to the release profile of the reference compositions. Diss. %: dissolution percentage.

[0021] Figure 4. Panel A: release profile of the composition of trazodone 150 mg, in which Contramid® was replaced with fully pre-gelatinized starch as described in Example 4, Test 6. Panel B: Test 7, composition prepared as described in Example 4. In both Panel A and Panel B, the release profiles were compared with the release profile of the reference composition. Diss. %: dissolution percentage.

[0022] Figure 5. Release profile of the 150 mg (Panel A) and 300 mg (Panel B) trazodone tablets prepared as described in Example 5, Test 8 and Test 9 respectively. Diss. %: dissolution percentage.

[0023] SUMMARY

[0024] The present invention relates to a pharmaceutical composition for the controlled release of trazodone comprising: trazodone or a pharmaceutically acceptable salt thereof, a fully pre-gelatinized starch and a chemically unmodified cellulose, where the ratio of fully pregelatinized starch to the chemically unmodified cellulose is comprised between 2:1 and 8:1 .

[0025] According to a preferred embodiment, the chemically unmodified cellulose is microcrystalline cellulose.

[0026] According to a further preferred embodiment, the pharmaceutical composition also comprises a chemically modified cellulose, such as, for example: hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses and carboxyalkylcelluloses. Among the hydroxyalkylcelluloses, the following may be selected: hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybuthylcellulose; among the hydroxyalkylmethylcelluloses, the following may be selected: hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybuthylmethylcellulose; among the hydroxyalkylalkylcelluloses, the following may be selected: hydroxypropylethylcellulose, hydroxypropylbuthylcellulose; and finally, among the carboxyalkylcelluloses, the following may be selected: carboxymethylcellulose, carboxyethylcellulose or carboxypropylcellulose, or mixtures thereof.

[0027] According to an embodiment of the invention, the fully pre-gelatinized starch is corn starch, potato starch or rice starch, even more preferably it is com starch.

[0028] A further embodiment of the invention relates to a matrix for the controlled release of drugs which comprises: fully pre-gelatinized starch, microcrystalline cellulose and chemically modified cellulose in the following percentages with respect to the total weight of the composition:

[0029] - fully pre-gelatinized starch: 25%-60%, preferably 28-43%,

[0030] - chemically unmodified cellulose, preferably microcrystalline cellulose, in a percentage comprised between 5% and 10% of the total mixture, chemically modified cellulose, preferably a hydroxyalkylmethylcellulose in a percentage comprised between 10% and 25%), and where the active ingredient is present in a weight percentage comprised between 20% and 50%, preferably comprised between 25% and 45%.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention allows preparing constant release formulations with constant release throughout the 24 hours following the administration thereof, thus suitable for a single daily administration (Once a Day: OAD). In particular, the tablets according to the invention allow to replace the reference OAD formulations, based on the use of Contramid®, a cross-linked starch with a high amylose content, with excipients that are easily available on the market.

[0033] In other words, the compositions according to the present invention maintain all the functional features of the reference compositions of trazodone containing Contramid®, such as the capacity for a constant release throughout 24 hours and the possibility of producing the tablet with a simple process, while at the same time improving and resolving any disadvantage related to the difficult replaceability of Contramid®.

[0034] The Applicant has achieved such a goal by using a fully pregelatinized, chemically unmodified starch, to which an amount of chemically unmodified cellulose comprised between 0 and 10% of the total weight of the formulation is added, preferably comprised between 1 and 9%, even more preferably comprised between 3 and 8%, even more preferably comprised between 4 and 7%, and between 5 and 6%, comprising all intermediate integer values or values with at least one decimal place, such as, e.g., 4.1 , 4.2, etc.

[0035] Therefore, when preferably present, the weight ratio of fully pregelatinized starch to chemically unmodified cellulose is comprised between 6:1 and 3:1 , more preferably comprised between 5.5:1 and 3.5:1 , even more preferably comprised between 5:1 and 4:1.

[0036] As mentioned above, chemically unmodified cellulose, when present, is microcrystalline cellulose, i.e., a purified form of partially depolymerized cellulose which is white, odorless and tasteless, made of porous particles. Together with the fully pre-gelatinized starch, they preferably constitute 20%-90% of the total weight of the composition, even more preferably they constitute 25-60%, or even more preferably 30%-55% of the total weight of the composition. In one embodiment thereof, the solid composition may also contain a carrier or vehicle (such as, for example, those identified in “Remington's Pharmaceutical Sciences, 18thEd., 1990). An example of a carrier is lactose, unmodified starch, dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar) in minimal quantities. In fact, these excipients are entirely optional and not necessary for obtaining the controlled release composition.

[0037] Forms of microcrystalline cellulose that are suitable for the object comprise, for example, the products known as: AVICEL-PH-101 , AVICEL-PH-102, AVICEL-PH-103, AVICEL-PH-105, AVICEL-PH-112, AVICEL-PH-113, AVICEL-PH-200, AVICEL-PH-301 and AVICEL SMCC (commercially available).

[0038] According to a further embodiment, the composition preferably also comprises chemically modified celluloses, in an amount comprised between 10% and 30% of the total weight of the tablet, more preferably comprised between 13 and 25%.

[0039] Chemically modified celluloses are selected from the group consisting of hydroxyalkylcelluloses, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybuthylcellulose, or hydroxyalkylmethylcelluloses, such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybuthylmethylcellulose, or they may be hydroxyalkylalkylcelluloses, such as hydroxypropylethylcellulose, hydroxypropylbuthylcellulose, or they may be a carboxyalkylcellulose, such as carboxymethylcellulose, carboxyethylcellulose and carboxypropylcellulose. Preferred alkylcelluloses, such as, for example, HPMC, are preferably comprised between 12 and 25% of the total weight of the tablet.

[0040] According to the embodiment comprising both chemically modified celluloses and chemically unmodified celluloses, the former are in a ratio comprised between 4:1 and 2:1 with respect to the chemically unmodified celluloses.

[0041] The fully pre-gelatinized starch used for the present invention is preferably selected from potato starch, corn starch or rice starch. Preferably, it is corn starch, composed of 20-30% amylose and amylopectin (70-80%). Pre-gelatinized starches of this type are readily available on the market and are for example: Lycatab® PGS, C^PharmGel™ (Cargill) etc.

[0042] With respect to Contramid®, these starches contain a lower percentage of amylose (20-30%). Furthermore, Contramid® is a crosslinked starch with a high amylose content, while the starches used in the invention are not cross-linked, and are chemically unmodified. As is known, in fact, the preparation of Contramid®, described in EP1305009B1 , requires as a starting reagent a starch with a high amylose content (at least 70%) (the average amylose content in the most common starches is about 40%) which is then cross-linked (e.g., with epichlorohydrin, adipic acid anhydride, sodium trimetasulfate and phosphorus oxychloride) in a very basic environment and then chemically modified, e.g., by hydroxypropylation and subsequently gelatinized.

[0043] The starches according to the invention have instead preferably a low amylose content and the preparation thereof requires only a full pregelatinization. Unexpectedly, they can ensure to the formulations according to the present invention with an appropriate combination of excipients, the same properties of a starch the preparation of which is more complex, such as Contramid®.

[0044] In fact, for example, Lycatab® PGS was not originally developed for controlled release, but as a diluent and antiaggregant for capsules and tablets, and as a binder for wet granulation and direct compression (Handbook of Pharmaceutical Excipients 7thedition 2012 “Starch, pregelatinized” pages 794-797) and therefore the controlled release features imparted to the formulation by starches with the same chemical- physical features as Lycatab® PGS according to the present invention, are fully unexpected.

[0045] The composition according to the present invention may comprise, in addition to pre-gelatinized starch in combination with microcrystalline cellulose and a chemically modified cellulose, further excipients e.g.: diluents, which may sometimes be referred to as “binders”, lubricants and glidants.

[0046] Among the diluents / binders that may be used are the following: other starches, or chemically modified celluloses, such as, for example, alkylcelluloses, inorganic salts, such as calcium phosphate, calcium carbonate, calcium acid phosphate; sugars, such as, for example, lactose, or polyols, such as, for example, mannitol, xylitol, etc.

[0047] Preferred among the used diluents / binders are chemically modified celluloses, preferably selected from the group consisting of: hydroxyalkylcelluloses, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybuthylcellulose, or hydroxyalkylmethylcelluloses, such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybuthylmethylcellulose, or hydroxyalkylalkylcelluloses, such as hydroxypropylethylcellulose, hydroxypropylbuthylcellulose, or carboxyalkylcelluloses, such as carboxymethylcellulose, carboxyethylcellulose and carboxypropylcellulose.

[0048] More preferably, the modified celluloses are hydroxyalkylcelluloses selected from: hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose.

[0049] In the formulation containing controlled release trazodone according to the invention, the weight ratio between the chemically modified cellulose, e.g., a hydroxyalkylcellulose, and the chemically unmodified cellulose, such as, e.g., microcrystalline cellulose, is preferably comprised between 3:1 and 1.5:1 , or even more preferably comprised between 2.5:1 and 2:1 .

[0050] Among the preferred glidants, the following may be used: silicon dioxide, colloidal silicon dioxide, talc etc. The preferred glidant is silicon dioxide.

[0051] Among the lubricating excipients, stearates may be used, such as for example magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, or even talc. A stearyl fumaric acid salt is preferred.

[0052] The composition is preferably in tablet form, or in any solid form suitable for oral administration.

[0053] Furthermore, the tablet may be filmed or not filmed. In any case, even if present, the film coating does not affect the release profile since it is added only for aesthetic purposes.

[0054] According to a particularly preferred aspect, the slow-release trazodone formulation has the following quantitative composition:

[0055] Table 1. Composition of the tablet containing trazodone according to the present invention.

[0056] The active ingredient trazodone, preferably trazodone hydrochloride, is preferably comprised between 25% and 45% of the total tablet. The film coating of trazodone tablets according to the invention is optionally present and does not affect the dissolution profile, as it was proven experimentally. In fact, such film coating is added only for aesthetic purposes.

[0057] According to a preferred embodiment with respect to Table 1 , the percentage of fully pre-gelatinized starch is preferably comprised between 25% and 55% of the total composition, and even more preferably comprised between 28% and 45%, depending on the amount of trazodone. Preferably, for compositions containing 300 mg trazodone (OAD) the % by weight of starch is comprised between 25 and 35%, while for the 150 mg dosage of trazodone, the % by weight of starch is preferably comprised between 40 and 45%.

[0058] The pharmaceutical composition comprising the mixture consisting of fully pre-gelatinized starch and chemically unmodified cellulose, e.g., microcrystalline cellulose, is found to have optimal compressibility, in particular, in the size of the commercial product, i.e. , for tablets with a weight comprised between 500 and 700 mg, which are also easily swallowable.

[0059] The present invention is therefore directed, according to a further embodiment, to the matrix for the controlled release of other drugs or active ingredients beside trazodone. Such matrix consists of a mixture of fully pre-gelatinized starch and chemically unmodified cellulose, in weight ratios (fully pre-gelatinized starch and unmodified cellulose) comprised between 6:1 and 3: 1 , more preferably comprised between 5.5:1 and 3.5:1 , even more preferably comprised between 5: 1 and 4: 1 and thus the controlled release tablet prepared with such combination, suitable for the constant release of an active ingredient throughout the 24 hours following the oral administration thereof.

[0060] In percentage terms with respect to the total weight of the composition, the tablet formulated with the controlled release matrix according to the invention has the following qualitative-quantitative composition:

[0061] Table 2. Composition of the formulation (controlled release matrix) comprising any active ingredient In the matrix or mixture of excipients for controlled release according to the present invention, the fully pre-gelatinized starch and the chemically unmodified cellulose, when present, are in a weight ratio comprised between 2:1 and 8:1 , more preferably comprised between 4:1 and 5:1 , comprised between 3:1 and 6:1 , more preferably comprised between 5.5:1 and 3.5:1 , even more preferably comprised between 4:1 and 5:1 .

[0062] The mixture of these two excipients preferably constitutes 30-60% of the total composition.

[0063] Even more preferably, the chemically unmodified cellulose is in an amount equal to or less than 10% of the total weight of the composition, preferably comprised between 6% and 9%, even more preferably comprised between 7% and 8.8%, with respect to the total weight of the composition. The preferred pharmaceutical form is that of a tablet comprising the composition of the invention.

[0064] The diluent / binder is preferably a hydroxyalkylcellulose and preferably is 12%-25% of the total weight of the tablet.

[0065] The film coating, where present, is only aesthetic and may be 2% of the total weight of the tablet.

[0066] The in vitro release of trazodone is preferably measured under standard conditions (USP paddle method apparatus type II) as described in U.S.P. ed. No. 44 (150 rpm, at 37±0.5[deg.]C, in 900 mL of a HCI / NaCI solution with pH 1 .2 for 1 hour followed by 23 hours in 50 mM phosphate buffer, pH 6).

[0067] The composition according to the invention enables the controlled release of trazodone starting 1 hour after intake, lasting for at least 24 hours after intake. Furthermore, in the hours following intake, the release of the drug is constant, not dependent on pH, and allows having an effective concentration of trazodone in the plasma, comprised in the therapeutic range thereof.

[0068] Experimental tests have proven that the in vitro release profiles of the compositions according to the invention, formulated as tablets, are comparable with those of the reference product (see Figure 5, Panels A and B).

[0069] The Applicant therefore believes that such formulations in the form of tablets with a total weight comprised between 500 and 700 mg, or even more preferably comprised between 600 and 700 mg, may be administered only once a day, ensuring a constant release throughout 24 hours, and may therefore represent a valid alternative to Once a Day trazodone tablets based on the use of Contramid®.

[0070] The Applicant therefore believes that replacing Contramid® with fully pre-gelatinized com starch or, even better, a mixture of the latter with chemically unmodified cellulose, preferably microcrystalline cellulose, more preferably in a weight ratio comprised between 6:1 and 3:1 , better if comprised between 5.5:1 and 3.5:1 , or even more preferably comprised between 5:1 and 4:1 , where the fully pre-gelatinized starch constitutes approximately 70% - 80% and the chemically unmodified cellulose the remaining 20-30%, is a valid alternative to the excipient represented by cross-linked starch with a high amylose content (Contramid®) capable of imparting to a tablet with a total weight comprised between 500 and 700 mg, or even more preferably comprised between 600 and 700 mg, an optimal compressibility and an in vitro and in vivo release profile that is superimposable to that of the reference drug (Trazodone OAD 150 and 300 mg).

[0071] Even more preferably, the mixture consists of fully pre-gelatinized starch, microcrystalline cellulose and chemically modified cellulose, preferably HPMC, in the weight ratios shown in Table 2.

[0072] Particularly preferred is the embodiment in which the matrix for the constant release of trazodone or any other active ingredient also comprises a chemically modified cellulose, as defined above, in a percentage comprised between 10 and 30% of the total weight of the tablet.

[0073] The active substance (or ingredient) usable with the controlled release matrix according to the invention is preferably selected from the group consisting of analgesics, antipyretics, anti-inflammatories, antidepressants, antiepileptics and antipsychotics, for example acetaminophen, diclofenac, ibuprofen, ketoprofen, indomethacin, naproxen, ketorolac, acetylsalicylic acid, toradol, perampanel, brivaracetam, valproic acid, carbamazepine, lacosamide, eslicarbazepine, fluoxetine, escitalopram, amitriptyline, trazodone, mirtazapine, venlafaxine, paroxetine, vortioxetine, olanzapine, risperidone, clozapine, alipiprazole, paliperidone, and the pharmacologically acceptable salts and mixtures thereof.

[0074] Advantageously, the tablets according to the present invention may be prepared with a direct process, i.e., by mixing all the ingredients and proceeding with compression. However, indirect processes, with wet or dry granulation of the mixture of ingredients and then compression, may also be adopted.

[0075] EXPERIMENTAL PART

[0076] Table 3. Materials

[0077] Methods. The in vitro Dissolution (or Release) Test involves the use of Apparatus 2 (Paddle Apparatus) described in U.S.P. ed. 44. And in E.P. ed. 11 .2. The following operating conditions were used: the tablets were placed in a “Japanese sinker”, paddle speed 150 rpm, at 37±0.5[deg.]C, in 900 mL of a HCI / NaCI solution with pH 1.2 for 1 hour followed by 23 hours in 50 mM phosphate buffer, pH 6. The % of trazodone released into the medium was measured by UV spectrophotometry with detection at 247 nm + / -2 nm in a cell with a 1 mm optical path.

[0078] Based on this measurement, the dissolution percentage indicated in the following tables and Figures with “% Diss.” is calculated. It was also verified that the film-forming agent had no impact on the dissolution test and therefore on the release of the drug, therefore, for convenience, the study was conducted on non-filmed tablets. Furthermore, the tests were initially conducted on the 150 mg dosage of trazodone and only in the event of a positive outcome of the test the applicability was also verified for the 300 mg trazodone dosage .

[0079] Example 1. Preparation of trazodone tablets according to Examples 1 and 3 of patent EP1931346 B1. The composition of trazodone HCI 300 mg was prepared as described in Example 1 of patent EP1931346 B1 (reference composition 300 mg).

[0080] Table 4 - Trazodone HCI 300 mg Formulation

[0081] The composition containing trazodone HCI 150 mg was prepared as described in Example 3 of patent EP1931346 B1 (reference composition

[0082] 150 mg).

[0083] Table 5 - Trazodone HCI 300 mg Formulation

[0084] The release profile of the prepared tablets containing 150 and 300 mg of trazodone hydrochloride was measured by the dissolution method described in Methods and is shown in Figures 1A and 1 B. This release profile was used as a reference standard for the formulations developed by the Applicant in this experimental part.

[0085] The release profiles are shown in the following table:

[0086] Table 6:

[0087] Example 2: Tests for replacing Contramid® with Starch 1500 (partially pre-gelatinized starch). In Test 1 , tablets with trazodone 150 mg were prepared by replacing Contramid® with the same amount of Starch 1500 (partially pregelatinized starch). The release profiles of Test 1 and that of the reference composition are shown in Figure 2, Panel A).

[0088] The test compositions were evaluated in comparison with the reference compositions by means of the Similarity Test (f2-test). The factor f2 measures the similarity of the two profiles and is calculated as follows: n being the number of time points, Rt and Tt the drug percentage (measured in dissolution) of the reference and test product at time t, respectively.

[0089] The test is adopted as a criterion for estimating the comparison between the in vitro dissolution profiles. FDA and EMA established that values of f2 comprised between 50 and 100 ensure similarity between the two dissolution profiles.

[0090] Table 7. Tests for replacing excipient Contramid® with Starch 1500. The dissolution test results for Test 1 are described in Table 8, which shows a low value of f2. Therefore, the amount of Starch 1500 was increased to 295 and 350 mg / tablet, respectively (Test 2 and Test 3), while the amounts of the other excipients were kept constant.

[0091] The total weight of the tablets was therefore 582 and 637 mg, respectively. The release profiles of the compositions prepared according to Test 2 and 3 are also shown in Table 8.

[0092] Table 8. Release times of the compositions of Tests 1 , 2 and 3

[0093] The tests performed demonstrated an improvement in the release profile with the first increase in the amount of Starch 1500. However, despite the increased size of the tablet, the release profile obtained with the highest amount of Starch 1500 still gave a non-optimal value of f2 (Figure 2, Panel B, Starch 1500 = 350 mg).

[0094] Example 3: Replacement of Contramid® with microcrystalline cellulose (MCC) or with fully pre-gelatinized starch.

[0095] In this test (Test No. 4) 150 mg trazodone hydrochloride tablets were prepared. Contramid® in the reference composition described in Example 1 was completely replaced with microcrystalline cellulose (MCC). The tablet had a total weight of 540 mg.

[0096] Tablets of 150 mg trazodone hydrochloride were then prepared, and Contramid® was replaced with fully pre-gelatinized starch (e.g., Lycatab® PGS), in the largest amount of Starch 1500 used in the tablets of Test 2, shown in Example 2 (350 mg) giving the best value of f2. The total weight of the tablet was therefore 637 mg.

[0097] Table 9. In vitro release profile of the tablet obtained according to Test 4 and Test 5

[0098] Table 9 shows that, by replacing Contramid® with MCC, the release profile moves away from that of the reference product, as also indicated by the low value of f2 (37) (see also Figure 3, Panel A), therefore this replacement is not advisable. As shown in Figure 3, Panel B, the release profile of Test 5 is closer to the release profile of the reference tablets, even if it is not yet satisfactory as indicated by the non-optimal value of f2. Therefore, simply replacing Contramid® with another type of starch or diluent does not ensure optimal results.

[0099] Example 4: Replacement of Contramid® with fully pre-gelatinized starch (Test No. 6)

[0100] 150 mg trazodone hydrochloride tablets were then prepared by replacing Contramid® with fully pre-gelatinized starch in the same amount as the reference tablets (Ex. 1 ). The other excipients were maintained in the same amounts and the final weight of the tablets, similarly, was kept the same (540 mg).

[0101] The release profile was found superimposable to that of the tablets of Example 1 (see Figure 4A and table 10), but the composition was found to have a low compressibility, not in line with the standard values needed for the scaling-up of the formulation.

[0102] Table 10: In vitro release profile of the tablet according to Test 6

[0103] This example demonstrates that the simple replacement of Contramid® with various other types of starch (both Starch 1500 and Lycatab® PGS), is not directly feasible.

[0104] In fact, Test 6 shows that the resulting mixture is not easily compressible, making difficult a possible scaling-up of the product, while in Test 1 (Example 2) the tablets do not appear to have a dissolution profile in line with that of the reference tablet.

[0105] In the next test, Test 7, the same composition present in the tablet of Test 6 was compressed with a smaller punch, thus obtaining a clear improvement in compressibility.

[0106] However, the dissolution profile of the 150 mg tablet, measured under standard conditions and shown in Figure 4B, still did not match that of the reference standard.

[0107] The release profile of the tablet obtained with Test 7 is shown in the following table.

[0108] Table 11 :

[0109] As may be seen in Table 11 , the value of f2 is not yet optimal.

[0110] Example 5. Preparation of controlled release trazodone formulations The tablet for Test 8 was then prepared with the composition indicated in Table 12.

[0111] Table 12: composition of the tablet of Test 8

[0112] The dissolution profile is shown in Figure 5A. Similarly, i.e., with the same HPMC / fully pre-gelatinized starch ratio (1 :2), the 300 mg Trazodone HCI tablet was prepared, to which the same amount of microcrystalline cellulose was added as in the 150 mg tablet.

[0113] Therefore, advantageously, in the tablets containing 150 mg and 300 mg trazodone according to the preferred embodiment, the fully pre- gelatinized starch to HPMC ratio remains the same, while the amount of chemically unmodified cellulose, added for compressibility purposes, remains constant.

[0114] The qualitative-quantitative formula of the tablet containing 300 mg trazodone HCI is shown in the following Table 13, the release profile in Figure 5B.

[0115] Table 13:

[0116] The release profiles, measured under standard conditions, were superimposable to those of the reference tablets prepared in Example 1 , confirming optimal results also in the values of f2 (both equal to 89).

[0117] The new formulations developed (comprising a film coating) were subjected to:

[0118] • ICH stability study (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use)

[0119] • Bioequivalence study in “Fasting condition”

[0120] • Bioequivalence study in “Fed condition”

[0121] The results of the studies demonstrated full bioequivalence between the reference formulations with Contramid® and the newly developed formulations of the invention.

Claims

CLAIMS1. A pharmaceutical composition for the controlled release of trazodone comprising:- trazodone or a pharmaceutically acceptable salt thereof,- a fully pre-gelatinized starch and- a chemically unmodified cellulose, wherein the ratio between fully pre-gelatinized starch and chemically unmodified cellulose is comprised between 2:1 and 8:1.

2. A pharmaceutical composition for the controlled release of trazodone according to claim 1 , wherein the ratio of such fully pregelatinized starch and such chemically unmodified cellulose is comprised between 4:1 and 5:1.

3. A pharmaceutical composition according to claims 1 -2, wherein the chemically unmodified cellulose is microcrystalline cellulose.

4. A pharmaceutical composition according to each of claims 1 -3, further comprising a chemically modified cellulose selected from: hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses and carboxyalkylcelluloses.

5. A pharmaceutical composition according to claim 4, wherein such hydroxyalkylcelluloses are selected from: hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybuthylcellulose; such hydroxyalkylmethylcelluloses are selected from: hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybuthylmethylcellulose; such hydroxyalkylalkylcelluloses are selected from: hydroxypropylethylcellulose, hydroxypropylbuthylcellulose; and wherein such carboxyalkylcelluloses are selected from: carboxymethylcellulose, carboxyethylcellulose and carboxypropylcellulose.

6. A pharmaceutical composition according to claim 5, wherein the chemically modified cellulose is a hydroxyalkylcellulose or a hydroxyalkylmethylcellulose and is selected from: hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose.

7. A pharmaceutical composition according to each of claims 1 -6, wherein the chemically modified cellulose is present in weight ratios with respect to the chemically unmodified cellulose comprised between 3:1 and 1.5:1 , more preferably between 2.5:1 and 2:1.

8. A pharmaceutical composition according to each of claims 1 -7, wherein such fully pre-gelatinized starch is com starch, potato starch or rice starch.

9. A pharmaceutical composition according to each of claims 4-8, wherein the weight ratio between trazodone, fully pre-gelatinized starch, chemically modified cellulose and chemically unmodified cellulose is about 3:5:2.5:1 .

10. A pharmaceutical composition according to each of claims 4-9, wherein the weight ratio between trazodone, fully pre-gelatinized starch, chemically modified cellulose and chemically unmodified cellulose is about 6:4:2: 1 .

11. A pharmaceutical composition according to each of claims 1 -10, wherein the salt of trazodone is trazodone HCI.

12. A pharmaceutical composition for the controlled release of trazodone according to claims 4-11 , comprising:- trazodone or the pharmaceutically acceptable salts thereof: 20%-50%, preferably 25%-45% by weight,- a fully pre-gelatinized starch 25%-60%, preferably 28%-45% by weight,- a chemically unmodified cellulose 5%-10%, preferably 6%-9% by weight,- a chemically modified cellulose 10%-25%, preferably 14%-22% by weight, with respect to the total weight of the composition.

13. A tablet comprising the pharmaceutical composition according to claims 1 -12.

14. A tablet according to claim 13, further comprising an external film coating.

15. A mixture of excipients for the controlled release of drugs comprising, with respect to the total weight of the mixture:- a fully pre-gelatinized starch in a weight ratio from 25% to 60%, preferably 28-43%,- a chemically unmodified cellulose, preferably microcrystalline cellulose, in a weight percentage from 5% to 10%,- a chemically modified cellulose, preferably a hydroxyalkylmethylcellulose, in a weight percent comprised from 10% to 25%, and wherein the active ingredient is in a weight percent comprised between 20% and 50%, preferably between 25% and 45%, with respect to the total weight of the composition.

16. A tablet comprising the mixture of excipients according to claim 15.

17. A tablet according to claim 16, wherein the active ingredient is selected from the group consisting of: analgesics, antipyretics, antiinflammatories, antidepressants, antiepileptics and antipsychotics.

18. A tablet according to claim 17, wherein the active ingredient is selected from the group consisting of: acetaminophen, diclofenac, ibuprofen, ketoprofen, indomethacin, naproxen, ketorolac, acetylsalicylic acid, toradol, perampanel, brivaracetam, valproic acid, carbamazepine, lacosamide, eslicarbazepine, fluoxetine, escitalopram, amitriptyline, trazodone, mirtazapine, venlafaxine,paroxetine, vortioxetine, olanzapine, risperidone, clozapine, alipiprazole, paliperidone.

19. A tablet according to claim 18, wherein the active ingredient is trazodone.

20. A tablet according to claims 16-19, further comprising an external film coating.

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