UA89168C2 - Modified release tablet of bupropion hydrochloride - Google Patents

Abstract

A modified-release tablet of bupropion hydrochloride comprising (i) a core comprising an effective amount of bupropion hydrochloride, a binder, a lubricant; and (ii) a control releasing coat surrounding said core; and (iii) a moisture barrier surrounding said control releasing coat, wherein the modified-release tablet is bioequivalent to Wellbutrin© or Zyban/WellbutrinSR tablets.

Description

This invention relates to a tablet with a modified release, which consists of pharmaceutically acceptable salts of bupropion, preferably bupropion hydrochloride.

Bupropion is an antidepressant that is chemically unrelated to tricyclic, tetracyclic selective serotonin reuptake inhibitors (SSRIs), or other known antidepressant agents.

This drug is similar to a psychostimulant in terms of its neurochemical and behavioral profiles in the body, but it is guaranteed not to produce stimulant effects in humans at clinically prescribed doses. Its structure closely resembles the structure of diethylpropion and belongs to phenylethylamines. It is defined as (5)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino|-1-propanone hydrochloride and has a non-proprietary name - amphebutamone hydrochloride. Bupropion hydrochloride is serially produced in an immediate-release form (UMePriipF) and in a delayed-release form (UeIIBshnipF 5A and 2uraPff)). UUePriiIPF 58 and 7urapf are chemically and pharmaceutically identical.

The neurochemical mechanism of bupropion's antidepressant action is not well understood. Bupropion does not inhibit monoamine oxidase. Bupropion affects chemicals inside the brain that nerves use to send messages to each other. These chemical messengers are called neurotransmitters. Neurotransmitters released by the nerves are reabsorbed by the nerves, which release them for reuse (re-uptake). Depression is thought to be caused by an imbalance in the amount of neurotransmitters that are released. Bupropion is thought to work by stopping the reuptake of the neurotransmitters dopamine, serotonin, and norepinephrine, an action that makes more dopamine, serotonin, and norepinephrine available to send messages to other nerves. Thus, bupropion is unique in that it acts primarily on dopamine, an effect not achieved by NSAIDs (eg, paroxetine (Rahib), fluoxetine (RgogasftF), sertraline (7o101j8)) or tricyclic antidepressants or TCAs (eg , amitriptyline (EIamikv)), imipramine (Toitapi!b), desipramine (MogrgatipFf))). Mayorship and M/ePrhygip? ZA are used to manage depression. 7urapFb has been approved as an adjunct to those patients who want to quit smoking. UuyiYirsnipF, which is an immediate-release formulation of bupropion, is prescribed three times a day with intervals of preferably 6 or more hours between doses. For patients requiring more than 30 mg of bupropion per day, each dose should not exceed 150 mg. This requires taking the pills at least 4 times a day with at least 4 hours between doses. The immediate-release formulation is defined by the fact that more than 7595 bupropion is released into the soluble medium within 45 minutes, and one of the main side effects of bupropion is the occurrence of paroxysmal seizures, which may be partially related to the immediate release of bupropion into the system. Thus, sustained-release drugs were developed to prevent paroxysmal attacks. Sustained-release drugs are prescribed twice a day.

In general, patient contact is a problem when multiple medication regimens are required, and it is especially problematic with depressed individuals. While sustained-release formulations have simplified the regimen and increased patient contact, there is still room for further simplification of the regimen and further improvement of patient compliance. The development of an approved stable formulation of modified-release bupropion for single administration was 6 steps forward.

Sustained-release bupropion tablets have been described previously. US Patent No. 4,687,660 discloses a tablet comprising a core and a coating, wherein the core consists of bupropion hydrochloride together with excipient(s) and additionally, but not necessarily, with an agent that increases blood osmotic pressure, and the shell consists of a water-insoluble, water-permeable, film-forming polymer (such as cellulose acetate), a pore-forming agent (such as inert lactose and sodium carbonate) and additionally, but not necessarily, a so-called water-permeable reinforcing agent (such as polyethylene glycol) and in addition, additionally, but not necessarily, with a plasticizer.

US Patent Nos. 5,358,970 and 5,427,798 describe a sustained-release formulation of bupropion hydrochloride based on matrix technology. The term matrix refers to a tablet in which the drug is embedded in an excipient that creates a solid core called the matrix. Diffusion of the drug occurs through this core. Because bupropion hydrochloride is unstable, the product described in the two prior patents requires a stabilizer to provide sufficient stability.

Such a stabilizer is an acidic compound, mainly cysteine hydrochloride. The main disadvantage of matrix systems is that they usually exhibit a first-order release profile. That is, first the particles of the drug that are on the surface of the tablet will dissolve, and the drug will be released quickly. After that, the drug particles, which are at distances that gradually increase from the surface of the tablet, will dissolve and be released by diffusion in the pores towards the outer surface of the tablet. Thus, the diffusion length of the drug will increase as the release process continues. Generally, it is preferable to achieve a zero or near zero order release profile than a first order release profile.

The zero-order release system provides a constant rate of drug release over a certain period of time. It is mainly used for drugs that have short half-lives, so that constant levels of combinations of active drugs in the blood can be maintained with fewer doses.

US Patent Mob. 589,553 and International Publication MeU/O 02/062299 specifically describe a once-daily capsule formulation with two populations of coated pills, each of which releases bupropion hydrochloride at different pH levels. One population of pills is coated so that the drug is released at a pH of about 4.8 or less. Drug release from this population of pills is expected in the upper gastrointestinal tract. Another population of pills is coated so that the drug is released at a pH level of 7 and above. The release of bupropion from this population is expected in the lower gastrointestinal tract. In one of the examples shown, the relative bioavailability of bupropion in relation to 7urapfb was only 4095 of the Stach coefficient and only 8095 of the AOSo-p coefficient. In another given example, the relative bioavailability of bupropion in relation to 2urapF was only 4895 and 5995 of the Stach and AOSo-i coefficients. These documents further describe the introduction of a third population of active uncoated pills that purposefully lead to further modification and improved release of bupropion. Based on the mean plasma concentration-time profile shown in Figures 3C and 4 of these documents, it is not apparent that the introduction of uncoated active pills would provide a bioequivalent once-daily formulation (base product is 2urapF)). Also, neither of these two documents provides any information regarding the stability of the medicinal product.

US Patent No. 033,686 describes a stabilizer-free, non-porous-forming, controlled-release tablet that includes a core consisting primarily of bupropion hydrochloride, a binder, and a lubricant; as well as a shell consisting of a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer. The product, which is obtained on the basis of the patent "686, is a product for taking twice a day.

US patents MoMob.096,341 and 6,143,327 both relate to the sustained release formulation of bupropion hydrochloride. The 341 patent provides a controlled-release tablet without a stabilizer and without a blowing agent, which includes a core consisting mainly of bupropion hydrochloride, a binder and a lubricant; as well as a shell consisting mainly of a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer. The '327 patent provides a stabilizer-free, non-porous-forming, controlled-release tablet comprising a core consisting primarily of bupropion hydrochloride, a binder, and a lubricant; and a controlled-release shell consisting primarily of a water-insoluble, water-permeable, film-forming polymer, a plasticizer and a water-soluble polymer, and a second shell that includes primarily a methacrylic polymer and a plasticizer. The formulation described in the '327 patent, however, does not meet EPA (Federal Drug Administration) standards for bioequivalence (see Example 8 in this document).

There is currently no approved and marketed stable once-daily formulation of bupropion. Thus, there is a need for a stable once-daily bioequivalent formulation of bupropion or a pharmaceutically acceptable salt thereof.

Definitions "Modified-release dosage forms" are defined by the U.S. Pharmacopoeia (US Pharmacopoeia) as those whose time and/or site release characteristics are selected to achieve therapeutic or convenience purposes not offered by conventional forms. The dosage form with extended release allows you to halve the frequency of doses or to improve the contact of the patient or the therapeutic result. The US Pharmacopoeia considers the terms controlled-release, extended-release, and sustained-release to be interchangeable with extended-release. Thus, the terms "modified release," "controlled release," "extended release," "sustained release," and "sustained release" are used interchangeably herein.

The term "a pharmaceutically acceptable salt of bupropion" includes salts that are physiologically acceptable to the patient. Such salts are usually prepared from inorganic acids or bases and/or organic acids or bases.

Examples of such acids and bases are well known to those skilled in the art. The use of bupropion hydrochloride is suggested, although the use of other pharmaceutically acceptable salts is within the scope and scope of the invention.

The term "effective dose" as used herein means a "Pharmaceutically Effective Dose". "Pharmaceutically effective dose" is a dose or amount of a pharmaceutically acceptable salt of bupropion that is sufficient to cause an appreciable biological response when ingested by a patient. Obviously, the exact therapeutic dose will depend on the age and condition of the patient, as well as the cause of the condition to be treated, and will be determined solely at the discretion of the physician.

The term "moisture-resistant layer" as used in this document is such a layer that prevents or delays the absorption of moisture. Bupropion hydrochloride is known to be highly hygroscopic and therefore relatively unstable and prone to decomposition over time, especially in high humidity conditions. The proportion of moisture barrier components and the amount of moisture barrier applied to the release control coating are such that this moisture barrier does not meet the United States Pharmacopoeia definition and requirements for an enteric coating. Preferably, the moisture-resistant layer consists of an enteric and/or acrylic polymer, preferably an acrylic polymer, additionally, but not necessarily, a plasticizer and a penetration enhancer. A penetration enhancer is a hydrophilic substance that allows water to penetrate without physically breaking the shell. The moisture resistant layer can additionally contain other conventional inert excipients that can improve the handling of the modified release formulation described herein.

The term "total impurities" used in this document is all decomposition products that occur after the decomposition of bupropion hydrochloride. "Decomposition products" include those listed on page 281 of the 26th edition

US Pharmacopoeia, and any other degradation products that may appear as peaks in the chromatogram during analysis.

Tablets with modified release, according to the present invention, are bioequivalents of tablets

Mueirshipb or 72urape/mMeiPriyipe5A. The term "bioequivalent" means that there is no significant difference in the rate and extent in which the active ingredient or active part in pharmaceutical equivalents or pharmaceutical alternatives is released at the site of action of the drug under the same molar dose and under the same conditions of a properly designed study. Where there is a significant difference in rate (for example, in individual sustained-release dosage forms), individual pharmaceutical equivalents or alternatives may be considered bioequivalent unless there is a significant difference in the rate at which the active ingredient or part and from each product is released at the site of action of the medicinal product. tool This is acceptable only if the difference in the rate at which the active ingredient or part is released at the site of action of the drug is significant and shown on the proposed label is not important to achieve effective concentrations of the drug in the body with long-term administration and is considered medically insignificant for this medicinal product.

The object of the proposed invention is a tablet with modified release, which consists of a pharmaceutically acceptable salt of bupropion, preferably bupropion hydrochloride. The advantage of the modified-release tablets according to the present invention, which is not achieved by the prototype tablets of UmeiYirshhipF or 72urapeF/lleyPriyipF ZA, is that the modified-release tablets provide a once-a-day regimen, are bioequivalent to the tablets available on the market- prototypes and do not show the influence of food.

One embodiment of the proposed invention is a modified-release tablet that consists of (I) a core that consists of an effective dose of a pharmaceutically acceptable salt of bupropion, a binder, and a lubricant; and (i) a release control shell surrounding said core; and (ii) a moisture-resistant layer surrounding said release-controlling shell; moreover, the modified-release tablet is bioequivalent and presents a dissolution profile such that no more than 2095, preferably about 295 to about 1895, more preferably about 4905 to about 890, and preferably about 595, of the bupropion content is released after about 2 hours hydrochloride, after about 4 hours releases from about 1595 to about 4595, preferably from about 2195 to about 3795, more preferably from about 2895 to about 3495, and more preferably about 3295 of bupropion hydrochloride content, after about 8 hours releases from about 4095 to about 9095 , preferably from about 60,905 to about 8,595, more preferably from about 6,895 to about 7,495 and preferably about 7,495 of bupropion hydrochloride content, and after about 16 hours releases at least about 8,095, preferably at least about 9,395, more preferably not less than about 9695 and preferably not less than about 99905 of bupropion hydrochloride content sob

In one embodiment of the invention, the moisture-resistant layer does not function as an enteric coating, as determined by the US Pharmacopoeia test, which requires that when a tablet with an enteric coating layer is placed in 0.1M NCI for one hour, the total amount of the drug does not exceed 1095, and not less than 7595 of the medicinal product was released within 45 minutes into the buffer solution of rnb.v.

In one embodiment of the invention, a pharmaceutically acceptable salt of bupropion comprises at least about 94% by weight of the weight of the core in the dry state. Preferably, the modified-release tablet according to the present invention contains from about 50 mg to about 450 mg of bupropion hydrochloride. In the best version, the tablets according to the present invention contain about 150 mg or 300 mg of bupropion hydrochloride.

In another embodiment of the invention, the amount of binder is preferably from about 1 to about 6, and more preferably about 3 weight percent of the weight of the core in the dry state. The binder is mainly polyvinyl alcohol.

In another embodiment of the invention, the lubricant is preferably from about 1 to about 6 and more preferably about 3 weight percent of the weight of the core in the dry state. Lubricants suitable for tablets according to the present invention may be selected from the group consisting of glyceryl behenate, stearic acid, hydrated vegetable oils, and any combination thereof.

In another embodiment, the release control shell consists primarily of a water-insoluble, water-permeable, film-forming polymer, and can range from about 35 to about 60 percent by weight of the dry release control shell.

Preferably, the amount of water-insoluble, water-permeable, film-forming polymer is about 50 percent by weight of the dry weight of the release control shell for a 150 mg dose and about 45 percent by weight of the dry weight of the release control shell for a 300 mg dose.

The water-insoluble, water-permeable, film-forming polymer may be selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl alcohol, and any combination thereof. The preferred water-insoluble water-permeable film-forming polymers are ethyl celluloses, which may be selected from the group consisting of RA 100 ethyl cellulose, RA 20 ethyl cellulose, and any combination thereof. The best water-insoluble, water-permeable, film-forming polymer is RA 100 grade ethyl cellulose.

In another embodiment of the invention, the amount of plasticizer is from about 6 to about 30 and preferably about 12 weight percent of the weight of the release control shell in the dry state.

Plasticizers suitable for tablets according to the present invention may be selected from the group consisting of polyols, organic esters, oils/glycerides, and any combination thereof. The best plasticizer is polyvinyl alcohol 1450.

In another embodiment of the invention, the amount of water-soluble polymer can range from about 25 to about 50 percent by weight of the dry release control shell. Preferably, the water-soluble polymer is about 43 percent by weight of the dry release control shell. The water-soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, and any combination thereof. The best water-soluble polymer is polyvinylpyrrolidone.

In another embodiment of the invention, the ratio between the water-insoluble, water-permeable, film-forming polymer, plasticizer and water-soluble polymer for a 150 mg tablet of bupropion hydrochloride with a modified release, according to the present invention, can range from about 3:1:4 to about 5:1:3, and , the best ratio is 4:1:3.

In another embodiment of the invention, the ratio between water-insoluble, water-permeable, film-forming polymer, plasticizer, and water-soluble polymer for a 30 mg modified-release bupropion hydrochloride tablet according to the present invention can range from about 7:2:6 to about 19:5:18, with , the best ratio is 13:4:12.

In another embodiment of the invention, the weight gain after coating the tablet core with a release control coating can range from 390 to about 3095 of the weight of the dry tablet core. For a 150 mg modified release tablet according to the present invention, the weight gain can range from about 1395 to about 16905 dry tablet core weight, with the best weight gain being about 1595 dry tablet core weight. For a 300 mg modified release tablet according to the present invention, the weight gain after application of the release control coating can range from about 895 to about 1095 of the dry core weight of the tablet, with the best weight gain being 995.

In another embodiment of the invention, the moisture-resistant layer consists of an enteric and/or acrylic polymer, a plasticizer and a penetration enhancer and has a ratio of about 13:2:5.

The enteric and/or acrylic polymer is predominantly an acrylic polymer, which in turn is predominantly a methacrylic acid copolymer, which is commercially available in the form of Eidgadiya ! 30 0-55. Although the amount of methacrylic acid copolymer can range from about 30 to about 90 wt. percent of the weight of the moisture-resistant layer in the dry state, it is best if the amount of methacrylic acid copolymer is about 6695 of the weight of the moisture-resistant layer in the dry state.

In another embodiment of the invention, the plasticizer can be selected from the group that includes polyols, organic esters, oils/glycerides, and any combination thereof. The best plasticizer for the moisture-resistant layer is a combination of a polyol and an organic ester. The best polyol in this combination is polyethylene glycol 1450, and triethyl citrate is the best organic ester.

The ratio of organic ester to polyol is 1:2. Preferably, the plasticizer is from about 1 to about 30 and most preferably about 10 percent by weight of the weight of the moisture resistant layer in the dry state.

In another embodiment of the invention, the penetration enhancer is a hydrophilic substance that can be selected from the group consisting of silicon dioxide, colloidal silicone, lactose, hydrophilic polymers, sodium chloride, aluminum oxide, colloidal aluminum oxide, silicon oxide, microcrystalline cellulose, and any of them combination The penetration enhancer is preferably silicon dioxide, which is from about 20 to about and preferably about 25 percent by weight of the weight of the moisture resistant layer in the dry state.

In another embodiment of the invention, the moisture-resistant layer is applied so that the weight gain after the application of the moisture-resistant layer is no more than about 69o, and preferably no more than about 2.595 of the tablet weight in the dry state for both 150mg and 300mg modified-release tablets, respectively to this invention.

In another embodiment, the modified-release tablet according to the present invention provides a stable composition of bupropion hydrochloride such that at least about 9595 and preferably at least about 97.595 and even 98.595 or even 9995 of bupropion hydrochloride remains stable after about 12 months of storage at a temperature of 257 "C22"C/relative humidity 60905590.

In another embodiment, the modified-release tablet according to the present invention provides a stable composition of bupropion hydrochloride, such that at least about 9595 and preferably at least about 97.595 and even 98.595 or even 9995 bupropion hydrochloride remains stable after 18 months of storage at a temperature of 25" Szh2"С/relative humidity 6095 z590.

In another embodiment of the invention, modified-release bupropion hydrochloride tablets, according to the present invention, are bioequivalent to U/ePriipF or 2ubape/lueiPrinipya 58 tablets and their effectiveness does not depend on food intake.

In another embodiment of the invention, the moisture-resistant layer significantly prevents or delays the absorption of moisture inside the tablet, thus increasing the stability of bupropion hydrochloride.

For a more complete understanding of the invention, the following is a detailed description with reference to the attached drawings, in which:

Figure 1A shows a graph depicting the dissolution profile of 150 mg modified-release bupropion hydrochloride tablets with three different release rates, according to one embodiment of the invention.

Figure 18 shows a graph of the dissolution profile of 300 mg of modified-release bupropion hydrochloride tablets with three different release rates, according to one of the embodiments of the invention.

Fig. 2A shows a graph of the statistical analysis of Relative Impact Factors (Neiaime Nezropze Ratiogv (AVE)) of the adjusted total content of impurities in 150 mg tablets of bupropion hydrochloride with a modified release, according to one of the variants of the implementation of the invention, which are stored at a temperature of 25"Сж2"С/ relative humidity 60902595 in bottles made of high-density polyethylene (sub-depeyu roiuetuepe (NORE)) (7sii, 40cm3 and Zosi, 100cm3).

Fig. 2B shows a graph of the statistical analysis of the Relative Impact Factors (Neiaime Nezropze ERasiogz5 (ARE)) of the adjusted total content of impurities in 30 mg bupropion hydrochloride tablets with a modified release, according to one of the variants of the invention, which are stored at a temperature of 25"Сх2"С/ relative humidity 6090-4595 in bottles made of high-density polyethylene (sub-depeyu roiue (puiIepe (NORE))) (7cm, 40cm3 and 30cm, 100cm3).

Figure 33A shows a graph of the average concentrations of bupropion in plasma according to the study of equivalence of dose activity after the appointment of 2 x 150 mg (daily) and 1 x 300 mg (daily) tablets of bupropion hydrochloride with a modified release, according to one of the variants of the invention.

Fig. 3B shows a graph of the average concentrations of hydroxybupropion in plasma according to the study of equivalence of dosage after the appointment of 2x150mg (daily) and 1x300mg (daily) tablets of bupropion hydrochloride with a modified release, according to one of the variants of the invention.

Fig. 3C shows a graph of the average concentrations of bupropion threoamino alcohol in plasma according to the dosage equivalence study after the appointment of 2 x 150 mg (daily) and 1 x 300 mg (daily) tablets of bupropion hydrochloride with a modified release, according to one of the variants of the invention.

Fig. 30 shows a graph of the average concentrations of bupropion erythroamino alcohol in plasma according to the study of equivalence of dose activity after the appointment of 2x150mg (daily) and 1x300mg (daily) tablets of bupropion hydrochloride with a modified release, according to one of the variants of the invention.

Fig. 4A shows a graph of the effect of food on the average concentration of bupropion in plasma after the appointment of one 150 mg tablet of bupropion hydrochloride with a modified release, according to one of the variants of the invention.

Figure 48 shows a graph comparing the average bupropion plasma concentrations shown in Figure 4A with the average bupropion plasma concentrations after the administration of one 15 omg prototype tablet (7urapf).

Fig. AC shows a graph comparing the average concentrations of hydroxybupropion in plasma after the administration of one 150 mg tablet of bupropion hydrochloride with a modified release, according to one of the variants of the invention, with the average concentrations of hydroxybupropion in plasma after the administration of one 150 mg tablet-prototype 7urapf).

Fig. 40 shows a graph comparing the average concentrations of bupropion treoamino alcohol in plasma after the appointment of a single dose of 150 mg bupropion hydrochloride tablets with a modified release, according to one of the variants of the invention, with the average concentrations of hydroxybupropion in plasma after the appointment of a single dose of 150 mg tablets-prototype 7urapf) .

Figure AE shows a graph comparing the average concentrations of bupropion erythroamino alcohol in plasma after a single dose of 150 mg bupropion hydrochloride tablets with a modified release, according to one of the variants of the invention, with the average concentrations of hydroxybupropion in plasma after a single dose of 150 mg tablets-prototype 7urapf) .

Fig. 5A shows a graph comparing the effect of food on the average concentrations of bupropion in plasma for 300 mg bupropion hydrochloride tablets with a modified release for a single intake per day, according to one of the variants of the invention.

Fig. 5B8 shows a graph comparing the effect of food on the average concentrations of hydroxybupropion in plasma for

ZbOmg tablets of bupropion hydrochloride with a modified release for single intake per day, according to one of the variants of the invention.

Fig. 5C shows a graph comparing the effect of food on the average concentrations of bupropion treoamino alcohol in plasma for 30 mg bupropion hydrochloride tablets with a modified release for a single intake per day, according to one of the variants of the invention.

Fig.50 shows a graph comparing the effect of food on the average concentrations of bupropion treoamino alcohol in plasma for 30 mg of bupropion hydrochloride tablets with a modified release for a single intake per day, according to one of the variants of the invention.

Fig.bA shows a graph of the average concentrations of bupropion in the blood plasma in a stationary state after multiple intakes once a day of 300 mg of bupropion hydrochloride tablets with a modified release, according to one of the variants of the invention, when taken by the patient on an empty stomach.

Figure 6B shows a graph comparing the average steady-state bupropion plasma concentrations as shown in Figure 5A with the average steady-state bupropion plasma concentrations after repeated administration of the prototype tablet UMeiYirshhip? on an empty stomach

Fig. 6C shows a graph comparing the average concentrations of hydroxybupropion in the blood plasma in the stationary state after repeated administration of 300 mg of modified-release bupropion hydrochloride tablets once a day, according to one of the embodiments of the invention, when taken by the patient on an empty stomach, with the average concentrations of hydroxybupropion in the plasma in the stationary state condition after repeated intake of the UMeiYirshhip prototype pill? on an empty stomach

Fig. 60 shows a graph comparing the average concentrations of bupropion treoamino alcohol in the blood plasma in a steady state after repeated administration of 300 mg bupropion hydrochloride tablets with a modified release once a day, according to one of the variants of the invention, when taken by the patient on an empty stomach, with the average concentrations of bupropion treoamino alcohol in the plasma in a stationary state after repeated intake of the prototype tablet UMeiYirshhip? on an empty stomach

Fig. 6E shows a graph comparing the average concentrations of bupropion erythroamino alcohol in the blood plasma in the stationary state after repeated administration of 30 mg bupropion hydrochloride tablets with a modified release once a day, according to one of the variants of the invention, when taken by the patient on an empty stomach, with the average concentrations of bupropion of erythroamino alcohol in plasma in a stationary state after repeated intake of the prototype tablet UMeiYirshhip? on an empty stomach

Fig. 7A shows a graph of the average concentrations of bupropion in the blood plasma in the stationary state after repeated administration of Зб0Омг tablets of bupropion hydrochloride with a modified release once a day, according to one of the variants of the implementation of the invention, on an empty stomach.

Figure 7B shows a graph comparing the average bupropion plasma concentrations at steady state, as shown in Figure 7A, with the average bupropion plasma concentrations at steady state after multiple 15 omg (twice daily) fasting 2urapF prototype tablets.

Fig. 7C shows a graph comparing the average concentrations of hydroxybupropion in the blood plasma in the stationary state after repeated administration of 300 mg of bupropion hydrochloride tablets with modified release once a day, according to one of the variants of the invention, on an empty stomach, with the average concentrations of hydroxybupropion in the blood plasma in the stationary state state after repeated intake of 15Omg (twice a day) prototype tablets 72urapb on an empty stomach.

Fig. 7O0 shows a graph comparing the average concentrations of bupropion threoamino alcohol in the blood plasma in a stationary state after multiple administration of 30 mg of bupropion hydrochloride tablets with a modified release once a day, according to one of the variants of the invention, on an empty stomach, with the average concentrations of bupropion threoamino alcohol in blood plasma in a stationary state after repeated intake of 150 mg (twice a day) of 2urapF prototype tablets on an empty stomach.

Fig. 7E shows a graph comparing the average concentrations of bupropion erythroamino alcohol in the blood plasma in the stationary state after repeated administration of 30 mg bupropion hydrochloride tablets with a modified release once a day, corresponding to one of the embodiments of the invention, on an empty stomach, with the average concentrations of bupropion erythroamino alcohol in the plasma of blood in a stationary state after repeated intake of 15O0mg (twice a day) of 72urapb prototype tablets on an empty stomach.

The described invention relates to a modified-release tablet having a core consisting of a pharmaceutically acceptable salt of bupropion and conventional excipients covered with a release-controlling shell of the pharmaceutically-acceptable bupropion salt and a moisture-resistant layer surrounding the release-controlling shell. The modified-release tablet according to the present invention is bioequivalent. 1. Core.

The modified-release tablet core includes an effective dose of a pharmaceutically acceptable salt of bupropion, a binder and a lubricant, and may contain conventional inert excipients. The amount of active drug may range from about 50 to about 90 weight percent of the dry weight of the tablet, and preferably from about 70 to about 90 weight percent of the dry weight of the tablet. A pharmaceutically acceptable salt of bupropion is preferably bupropion hydrochloride.

A tablet contains an amount of bupropion hydrochloride that can range from about 50 mg to about 450 mg. It is better if the tablet consists of 150mg or ZbOmg of bupropion hydrochloride. For a 150 mg tablet, the amount of bupropion hydrochloride is about 78 percent by weight of the dry weight of the tablet. For

The amount of bupropion hydrochloride in ZbOmg tablets is about 83 percent by weight of the tablet weight in the dry state. For 150mg and 300mg modified-release bupropion hydrochloride tablets, according to the present invention, the amount of bupropion hydrochloride is about 94% by weight of the core weight in the dry state for each of these forms.

A binder (also sometimes called a tackifier) is added to the mass of the drug and excipient to ensure the formation of granules and tablets with the required mechanical strength.

Binders can be added to the formulation in various ways: (1) as a dry powder that is mixed with other ingredients prior to wet sintering, (2) as a solution used as a sintering fluid in the wet sintering process, called a soluble binder, and (3) ) as a dry powder that is mixed with other ingredients before compaction. In this form, the binder is called a dry binder. Soluble binders are generally considered to be the most effective and thus are the most common way to introduce a binder into granules. The binder used herein is in the form of a soluble binder.

Examples of binders suitable for the core include, but are not limited to, water-soluble polymers such as modified starch, polyvinylpyrrolidone, cellulose derivatives (such as, for example, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), and polyvinyl alcohol) . The amount of binder can range from about 0.5 to about 15 percent by weight of the tablet in the dry state, preferably from about 1 to about 6 percent by weight of the tablet in the dry state, and more preferably about 3 percent by weight of the tablet in the dry state . For 150 mg and 30 mg tablets, the amount of binder may preferably be from about 1 to about 6 percent by weight of the dry weight of each tablet, and more preferably about 3 percent by weight of the dry weight of each tablet. The best binder is polyvinyl alcohol.

Lubricants are added to therapeutic formulations to ensure that the tablet is formed and pushed with a low coefficient of friction between the solid and the mold wall. A high coefficient of friction in the tablet manufacturing process can cause a number of problems, including inadequate tablet quality (destruction of the pressed powder blank or even crushing of the tablets during the extrusion process and vertical scratches on the edges of the tablet), and can even stop production. Thus, lubricants are added to almost all tablet formulations, including the bupropion hydrochloride tablet formulation described herein. Examples of lubricants that are suitable for the core include (but are not limited to) glyceryl behenate, stearic acid, hydrated vegetable oils (such as hydrated cottonseed oil (beegoyehF), hydrated soybean oil (beegoyeh? NM), and hydrated soybean oil and hydrated castor oil oil (biegoiechF K)), stearic alcohol, leucine and polyethylene glycol (MU 4000 and above). The lubricant is mainly glyceryl behenate. The amount of lubricant may range from about 1 to about 5 weight percent of the dry tablet weight, preferably from about 2 to about 3 weight percent of the dry tablet weight, and more preferably about 2.5 weight percent of the dry tablet weight. For the 150mg and 300mg modified-release tablets of the present invention, the lubricant is about 2.5% by weight of the dry weight of the tablet, preferably from about 1 to about 6% by weight of the dry weight of the core, and more preferably about weight percentages of the kernel mass in the dry state for both forms.

At this stage, the core formulation is an immediate release formulation that results in 10095 bupropion hydrochloride dissolution within 1 hour (data not shown). Ideally, the core consists only of an effective pharmaceutical amount of a pharmaceutically acceptable salt of bupropion, a binder, preferably polyvinyl alcohol, and a lubricant, preferably glyceryl behenate. However, if necessary, additional inert excipients that meet the objectives of the invention may be added to the core composition.

Additional inert excipients may be added to facilitate preparation and/or improve patient tolerability of the final (final) modified-release bupropion hydrochloride dosage form as described herein. Additional inert excipients are well known to those skilled in the art and can be found in relevant literature, for example, in the Handbook of Medicinal Excipients. Examples of such excipients include (but are not limited to) spray-dried lactose, sorbitol, mannitol, and any cellulose derivatives.

Preferably, the granules that will be compressed to form the modified release tablet core of the disclosed invention will be made using a wet granulation process. Primarily, wet granulation involves mixing a powder (active drug), usually in a liquid (soluble binder), followed by drying. To form granules that will eventually be compressed into tablet cores, bupropion hydrochloride is first granulated, preferably together with a soluble binder in a granulator, preferably, but not necessarily, in a fluidized bed granulator, such as, for example, a fluidized bed granulator manufactured by Sai (Germany ) or Aegotais (Switzerland). The binder, preferably polyvinyl alcohol, is first dissolved or dispersed in a suitable solution, preferably water. The binder is then sprayed on top of the drug in a granulator, preferably a fluidized bed granulator. Alternatively, granulation can also be carried out in a conventional mixer or a high shear mixer. If necessary, additional inert excipients, such as, for example, a filler, may be mixed with the bupropion hydrochloride prior to the granulation step.

The formed granules are then dried and then sieved before mixing the granules with the lubricant. It is best if the dried granules are sifted through a sieve with a mesh size of 1.4 mm. The screened granules are then mixed with a lubricant and, if necessary, with any other additional inert excipient that can improve the processing of the modified release tablets according to the present invention. Mixing of the granules with the lubricant and, if necessary, with any other additional inert material, such as, for example, a glidant, may be carried out in an M-blender or any other suitable mixing device. Glidants improve the flowability of the powder. This is especially important when making tablets at high production speeds and in the direct compression process. However, due to the high requirement for appropriate flowability, the glident is often also added during granulation before the production of tablets. The mixed granules are then pressed into tablets and are further called tablet cores. Tablet cores can be obtained using standard techniques and equipment well known to those skilled in the art. Ideally, but not necessarily, the tablet cores are produced using a rotary press (also called a multi-station press) equipped with suitable dies. 2. Shells of tablets.

The tablet cores are coated in two stages. The release control coating is applied directly to the surface of the tablet cores and performs the function of controlling the release of a pharmaceutically acceptable salt of bupropion. A moisture resistant layer is applied directly to the surface of the release control shell to prevent or delay moisture absorption. 2.1 Release Control Shell.

A release control shell is a semipermeable shell consisting of a water-insoluble water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer.

Examples of water-insoluble, water-permeable, film-forming polymers used for the release control shell include (but are not limited to) cellulose ethers, cellulose esters, polyvinyl alcohol. The best water-insoluble water-permeable film-forming polymers are ethyl celluloses, which may be selected from the group consisting of RA 100 ethyl cellulose, ethyl cellulose grade

RA 20 and any combination thereof. The preferred water-insoluble, water-permeable, film-forming polymer is RA 100 grade ethyl cellulose. The amount of water-insoluble, water-permeable, film-forming polymer can range from about 1 to about 8 weight percent of the dry tablet weight, and preferably from about 2 to about 6 weight percent of the dry tablet weight . For a 150 mg modified-release bupropion hydrochloride tablet according to the present invention, the amount of water-insoluble, water-permeable, film-forming polymer may range from about 3 to about 6 percent by weight of the dry weight of the tablet. Preferably, the amount of water-insoluble, water-permeable, film-forming polymer is about 6.3 weight percent of the weight of the tablet in the dry state. With respect to the release control shell itself, the amount of water-insoluble, water permeable, film-forming polymer can range from about 35 to about 60 percent by weight of the dry release control shell. Preferably, the amount of water-insoluble, water-permeable, film-forming polymer is about 50 percent by weight of the weight of the release control shell in the dry state. For a 30mg tablet of bupropion hydrochloride with a modified release, according to the present invention, the amount of water-insoluble, water-permeable, film-forming polymer can vary from about 2 to about 5 percent by weight! mass of the tablet in the dry state. Preferably, the amount of water-insoluble, water-permeable, film-forming polymer is about 3.6 weight percent of the weight of the tablet in the dry state. With respect to the release control shell itself, the amount of water-insoluble, water-permeable, film-forming polymer is about 45 percent by weight of the dry release control shell.

Plasticizers are usually added to the compositions of film shells to modify the physical properties of the polymer in order to make it more suitable for use. The amount and choice of plasticizer contribute to tablet hardness and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. One of the important properties of plasticizers is their ability to make the shell elastic and resilient, thus reducing the brittleness of the shell. Examples of plasticizers that can be used for the release control coating described herein include (but are not limited to) polyols such as polyethylene glycol of various molecular weights, organic esters such as diethyl phthalate or triethyl citrate, and oils/glycerides , such as fractionated coconut oil or castor oil. The amount of plasticizer for the release control coating can range from about 0.5 to about 2 weight percent of the dry tablet weight. The best plasticizer is polyethylene glycol 1450. For a 150 mg modified-release bupropion hydrochloride tablet according to the present invention, the amount of plasticizer in the release-controlling shell is

may range from about 1 to about 1.5 weight percent of the weight of the tablet in the dry state. Preferably, the amount of plasticizer is about 1.5 percent by weight of the weight of the tablet in the dry state. For a 300 mg bupropion hydrochloride modified release tablet according to the present invention, the amount of plasticizer can range from about 0.5 to about 2 percent by weight of the dry weight of the tablet.

For the 150 mg and 300 mg dosage forms, the plasticizer preferably comprises from about 6 to about 30 weight percent of the dry weight of the release control shell, and preferably about 12 weight percent of the dry weight of the release control shell.

Examples of water-soluble polymers suitable for release control coatings include (but are not limited to) polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropylcellulose.

The best water-soluble polymer is polyvinylpyrrolidone, the amount of which can range from about 1.5 to about b weight percent of the weight of the tablet in the dry state. With respect to the release control shell itself, the amount of water soluble polymer can range from about 25 to about 55 percent by weight of the release control shell in a dry state. For a 150 mg bupropion hydrochloride modified-release tablet according to the present invention, the amount of water-soluble polymer may range from about 3 to about 5 weight percent of the dry weight of the tablet or about 25 to about 50 weight percent of the dry weight of the release control coating condition For

In a 30 mg bupropion hydrochloride modified-release tablet according to the present invention, the amount of water-soluble polymer may range from about 2 to about 5 weight percent of the dry weight of the tablet and about 43 weight percent of the dry weight of the release control coating.

The ratio of water-insoluble, water-permeable, film-forming polymer, plasticizer, and water-soluble polymer for a modified-release bupropion hydrochloride 150 mg tablet according to the invention described herein may range from about 3:1:4 to about 5:1:3.

The best ratio is about 4:1:3. For a 300 mg bupropion hydrochloride modified release tablet according to the invention described herein, the ratio of water-insoluble, water-permeable, film-forming polymer, plasticizer, and water-soluble polymer may range from about 7:2:6 to about 19:5:18. The best ratio is around 13:4:12.

In general, the release control coating is prepared and applied as follows.

A water-insoluble, water-permeable, film-forming polymer, preferably ethyl cellulose, and a plasticizer, preferably polyethylene glycol 1450, are dissolved in an organic solution, such as a mixture of ethyl alcohol and isopropyl alcohol. A plasticizer, preferably polyvinylpyrrolidone, is then added until a homogeneous mixture is achieved. The resulting release controlled coating solution is then sprayed onto the tablet cores using a tablet coating machine, fluid bed granulator, or any other suitable coating equipment well known to those skilled in the art until the desired weight gain is achieved. The tablet cores, coated with a release-controlling coating, are then dried before a moisture-resistant coating is applied.

It is understood by those skilled in the art that by controlling permeability it is possible to control the release of bupropion hydrochloride and/or the amount of coating that is applied to the tablet cores. The permeability of the release-controlling coating can be varied by varying the ratio of water-insoluble, water-permeable, film-forming polymer, plasticizer, and water-soluble polymer and/or the size of the coating applied to the tablet cores. A more sustained release is typically achieved with a larger amount of water-insoluble, water-permeable, film-forming polymer. Addition of other excipients to the tablet core can also alter the permeability of the release-controlling coating. For example, if the tablet core is required to additionally include a blowing agent, the amount of plasticizer in the release-controlling shell must be increased to make the shell more ductile, because the pressure exerted by the less plastic shell on the side of the blowing agent may rupture the shell. In addition, the ratio between water-insoluble, water-permeable, film-forming polymer and water-soluble polymer may also need to be varied depending on which - faster or slower - dissolution and/or release profile is desired.

Depending on the desired dissolution or release profile in the body, the weight gain after application of the release control coating to the tablet core can range from about 3 to about 30 percent by weight of the dry weight of the tablet core. For a 150 mg bupropion hydrochloride modified release tablet according to the present invention, the weight gain can range from about 13 to about 16 weight percent of the dry weight of the tablet core. A weight gain of about 15 percent by weight of the dry tablet core weight is best. For a 300 mg bupropion hydrochloride modified release tablet according to the present invention, the weight gain can range from about 8 to about 10 percent by weight of the dry weight of the tablet core. A weight gain of about 9 percent by weight of the dry tablet core weight is best. 2.2 Moisture-resistant layer.

The moisture resistant layer is applied directly to the release control shell and consists of an enteric and/or acrylic polymer, a penetration enhancer, and optionally, but not necessarily, a plasticizer.

An enteric polymer is mainly an acrylic polymer. The acrylic polymer is mainly a copolymer of methacrylic acid type C (poly(methacrylic acid, methyl methacrylate) 1:1| available on the market under the trade name Epidgadikiu (for example, Eidgadii I 30 0-55). The methacrylic acid copolymer is present in an amount that can vary from about 1 to about 3% by weight of the tablet in the dry state and from about 55 to about 70 percent by weight of the moisture-resistant layer in the dry state.For a 150 mg bupropion hydrochloride modified-release tablet according to the present invention, the amount of methacrylic acid copolymer can range from about 2 to about 3 weight percent of the dry tablet weight. In a preferred embodiment, the amount of methacrylic acid copolymer is about 2.5 weight percent of the dry tablet weight. With respect to the moisture-resistant layer itself, the amount of methacrylic acid copolymer is preferably from about 30 to about 90 weight percent percent of the weight of the moisture-resistant layer in the dry state and in preferably, about 66 percent by weight of the weight of the moisture-resistant layer in the dry state. For a 300mg modified-release bupropion hydrochloride tablet according to the present invention, the amount of methacrylic acid copolymer can range from about 1.5 to about 3% by weight of the dry weight of the tablet. It is best if the amount of methacrylic acid copolymer is about 2 percent by weight of the weight of the tablet in the dry state. With respect to the shell itself, the amount of methacrylic acid copolymer is preferably from about 30 to about 90 percent by weight of the weight of the moisture-resistant layer in the dry state, and more preferably about 66 percent by weight of the weight of the moisture-resistant layer in the dry state for a 300 mg modified-release tablet according to the present invention.

Those skilled in the art know that methacrylic acid copolymers tend to become brittle and thus require a plasticizer. Examples of plasticizers suitable for the release control coating described herein include (but are not limited to) polyols such as polyethylene glycol of various molecular weights, organic esters such as diethyl phthalate or triethyl citrate, and oils/ glycerides such as fractionated coconut oil or castor oil. The best plasticizer consists of a combination of triethyl citrate and polyvinyl alcohol 1450. The ratio of triethyl citrate to polyvinyl alcohol 1450 is about 1:2. The plasticizer is present in an amount that can range from about 0.2 to about 0.5, and preferably from about 0.2 to about 0.4 weight percent of the dry weight of the tablet. The plasticizer is about 0.35 percent by weight of the weight of a 150 mg tablet in the dry state and from about 0.2 to about 0.4 percent by weight of the weight of a 30 mg tablet in the dry state. With respect to the moisture-resistant layer itself, the plasticizer preferably comprises from about 1 to about 30 percent by weight of the weight of the moisture-resistant layer in the dry state, and more preferably about 10 percent by weight of the weight of the moisture-resistant layer in the dry state for 150mg and 300mg bupropion hydrochloride modified-release tablets according to the present invention . Specialists are well aware that, depending on the given main function, excipients used in tablets are classified into different groups. However, one excipient can affect the properties of a medicinal product or tablet in different ways, and many substances used in tablet formulations can thus be described as multifunctional. Thus, polyvinyl alcohol 1450, which is used in the plasticizer combination for the moisture resistant layer, serves not only to increase the hydrophilicity of the moisture resistant layer, but also acts as a gliding agent.

In addition to polyvinyl alcohol 1450, the penetration enhancer also acts as a gliding agent and also increases the hydrophilicity of the moisture resistant layer. The penetration enhancer is a hydrophilic substance and can be selected from the group consisting of silicon dioxide, colloidal silicone, lactose, hydrophilic polymers, sodium chloride, aluminum oxide, colloidal aluminum oxide, silicon oxide, microcrystalline cellulose, and any combination thereof.

Silicon dioxide is the best penetration enhancer. The amount of penetration enhancer can range from about 0.5 to about 1 weight percent of the dry weight of the tablet and is about 25 weight percent of the dry weight of the moisture resistant layer. For a 150 mg tablet of bupropion hydrochloride with a modified release, according to the present invention, the amount of penetration enhancer is about 0.9 weight percent of the weight of the tablet in the dry state and from about 20 to about 40 and preferably about weight percent of the weight of the moisture resistant layer in the dry state. For ZbOmg modified-release bupropion hydrochloride tablets, according to the present invention, the amount of penetration enhancer can range from about 0.5 to about 1 weight percent of the weight of the tablet in the dry state and is preferably from about 20 to about 40 and preferably about 25 weight percent of the weight moisture-resistant layer in a dry state.

The ratio between methacrylic acid copolymer, plasticizer and penetration enhancer is preferably about 13:2:5.

In general, the preparation and application of a moisture-resistant layer is carried out as follows. A plasticizer, preferably a combination of polyvinyl alcohol 1450 and triethyl citrate, is first added to the water and the mixture is mixed until smooth. Copolymer of methacrylic acid, mainly Etsygadivb | 30 0-55, then sieved and added to the plasticizer mixture and mixed until smooth. In a separate container, the penetration enhancer, preferably silicon dioxide, is dissolved in water until a homogeneous mixture is reached.

The mixture of plasticizer and methacrylic acid copolymer is then combined with the penetration enhancer solution and mixed until homogenous. The resulting moisture resistant coating solution is then sprayed onto tablet cores that are coated with a release control coating using a tablet coating machine, fluidized bed granulator, or any other suitable coating equipment well known to those skilled in the art until the desired weight gain Tablets covered with a moisture-resistant layer are then dried before packaging.

The moisture resistant layer is applied to the cores of the release control coated tablets in such a way that the weight gain is not more than about 6 and preferably not more than about 2.5 weight percent of the dry tablet weight for 150mg and 30mg bupropion hydrochloride tablets with modified release according to the present invention. The amount of moisture-resistant coating applied does not render the bupropion hydrochloride modified-release tablet described herein resistant to gastric juice and has no significant effect on the drug release characteristics.

The moisture-resistant layer in this use does not perform the function of an enteric coating. Although the copolymer of methacrylic acid, Etsyagadiyu 1 30 0-55, is indicated and used in enteric coating formulations, its functionality depends on the composition and amount of applied material.

Those skilled in the art know that an enteric coating is applied where the drug may be destroyed or deactivated by gastric fluid, or where the drug may irritate the gastric mucosa. In order to meet the requirements for an enteric coating, the test described in the US Pharmacopoeia (Method A or B) stipulates that after 2 hours in an acidic medium (0.1 M HC)

no individual values, at least 6 experiments, exceed 1095 dissolved active drug and not less than 7595 dissolved within 45 minutes in pH 8. Although an acidic environment does not adversely affect bupropion hydrochloride, and it does not irritate the gastric mucosa, the moisture-resistant layer does not meet this requirement for the following reasons: (1) to obtain enteric integrity with a film that contains Etzgadium I 30 0-55, it is recommended that the weight gain was from about 695 to about 895 due to dry polymer per unit dose. The amount of Espagadicu I 30 0-55 solids applied to the core of the release controlled tablet is not more than 69o and preferably not more than 2.595, (2) if enteric integrity is required, the solubility test for the finished product (i.e., moisture-resistant tablet cores) after 2 hours would not result in a limit of no more than 2090, and (3) analytical tests performed on the final double-coated product show that the product does not meet all of the test requirements for an enteric-coated product shell as determined by US Pharmacopoeia test methods. Since the moisture-resistant layer is applied directly to the release-controlling coating, tests were performed to determine whether the moisture-resistant layer applied directly to the immediate-release tablet cores would function as an enteric coating.

Tests show that after 1 hour more than 4095 bupropion hydrochloride is released from the tablet cores in 01 NOV and thus does not meet the USP definition for an enteric coating (see

Example 2). The functionality of the moisture-resistant layer was also confirmed by determining the moisture content using the Karl-Fischer (KF) test on separately coated release-controlling coating and moisture-resistant layer tablet cores under accelerated conditions (at a temperature of 40°C/RH 75952590) in an open glass cup for 10 days (see Example 2). The results show that the moisture content of tablet cores coated with a release control coating is higher than that of tablet cores coated with a moisture resistant layer. Taken together, these data define the functionality of the moisture-resistant layer as a shell that significantly prevents or delays the absorption of moisture, and not as an enteric shell as defined by the US Pharmacopoeia.

The tablet according to the present invention provides a sustained release of bupropion hydrochloride, although the composition does not contain any pore-forming substance. The aforementioned composition also provides a stable bupropion hydrochloride composition such that after about 2 hours no more than about 2095, preferably about 295 to about 1895, more preferably about 4956 to about 895 and most preferably about 595 of bupropion hydrochloride content is released , after about 4 hours releases from about 2095 to about 45905, preferably from about 2195 to about 3795, more preferably from about 2895 to about 3495 and most preferably about 3295 of bupropion hydrochloride content, after about 8 hours releases from about 4095 to about 9095 , preferably from about 6095 to about 8595, more preferably from about 68956 to about 7495 and most preferably about 7495 of bupropion hydrochloride content, and after about 16 hours is released not less than about 8095, more preferably not less than about 9395, more preferably not less than about 9695 and preferably not less than about 9995 of the bupropion hydrochloride content.

A positive effect on the stability of the modified-release bupropion hydrochloride tablet, according to the composition described in this document, is evident in tests performed to evaluate total impurities in 150mg or 300mg dosage forms for b months under accelerated conditions (at a temperature of 40"Сх2 "C/relative humidity 75952595), as well as during 12 months and 18 months of long-term stability at a temperature of 257"C2"C/relative humidity 60952595. Stability tests showed reduced indicators (relative to M/eiYiriyip 5A) of total impurities in tablets.

In high-density polyethylene bottles of 7 ci, 40 cm3 and 30 ci, 100 cm3, for 150 mg and 30 Omg modified-release tablets according to the present invention, for example, total impurities should not be more than about 2.5 percent by weight of the amount bupropion hydrochloride in a tablet, preferably not more than about 1.595, preferably not more than about 0.695 during at least 12 months of long-term storage under stable conditions: at a temperature of 25"C2"C/RH 60955905.

During 18 months of long-term stability at a temperature of 25°C2°C/RH 6090°590, total impurities should not be more than about 2.5% by weight of the amount of bupropion hydrochloride in the tablet, preferably not more than about 1.5, preferably not greater than about 0.7 weight percent of the amount of bupropion hydrochloride in the tablet. Thus, a modified release bupropion hydrochloride tablet, according to the present invention, contains at least about 9595 weight ratio and more preferably at least 9895 or even at least 9995 bupropion hydrochloride of nominal quality after storage for 12 or 18 months of long-term stability under conditions of temperature and humidity normal for pharmacies and medicine cabinets, i.e. room temperature and 35-6095 humidity. Thus, a pharmaceutical preparation, such as a tablet, will still retain at least 9595 of its potency and preferably at least 9895 or even 9995 of its potency after storage for one year at room temperature (1527-2572) and 35-6095 humidity. For example, if a tablet initially contains 300 mg of bupropion hydrochloride (amount according to the label), after one year of storage, at least 285 mg of bupropion hydrochloride, and preferably at least 294 mg or more, will remain in the tablet.

The moisture content according to the Kf method and the total amount of impurities of bupropion hydrochloride for a 150 mg tablet, according to the present invention, when stored under accelerated conditions for at least 6 months for bottles made of high-density polyethylene with a volume of 7 soshpi, 40 cm3 should not be more than about 195 Bottles and

Zb0Omg tablets of the same configuration stored under the same accelerated conditions should have a Kf moisture content of not more than about 195 and total impurities not more than about 0.695 for at least 6 months. 15O0mg tablets stored in high density polyethylene bottles of 30 cc, 100cm3 should have a CF moisture content of not more than about 195 and total impurities not more than about 1.295 when stored under accelerated conditions for at least 6 months . ZOOmg tablets stored in the same configuration and under the same conditions for the same period of time should have a Kf moisture content of no more than about 190 and total impurities no more than about 0.895. When stored in an open glass cup, the moisture content according to the KF method for 30 mg of modified-release bupropion hydrochloride tablets according to the present invention should not be more than about 0.890 after

Of days and preferably greater than about 0.4595 after 10 days of storage under accelerated conditions. When stored in a tightly closed glass bottle, the moisture content according to the Kf method should not be more than about 0.4590 after 3 days and preferably more than about 0.495 after 10 days.

The following examples illustrate this invention and do not limit the scope of the invention.

Example 1 1. Composition of tablets with modified release.

Three different core formulations were prepared for each 150 mg and 300 mg bupropion hydrochloride modified release tablet as shown in Table 1:

Table 1

Core composition

Ingredients A | in | with | 64 | in Her village

Bupropion hydrochloride 150/81.1 150/82.4 150/79 300/79 300/87.6 300/83.5 5.3/2.86 5.3/2.9 5.3/2.8 10.6/2.8 10.6/3.1 10.6/2.95

Lubricant With | 4.7/2.54 4.7/2.58 4.7/2.46 9.4/2.48 9.4/2.74 9.4/2.61 160/86.48 160/87.91 160/83.77 320/84.43 320/93.47 320/89.02 in the dry state 1 Indicators are the ratio of the ingredient to the weight of the tablet mg/9o dry state 2 Polyvinyl alcohol

Z Glyceryl behenate (Sotriot! 888 ATO) 4 Evaporation during drying

The water is first heated to 602457"C. The binder (polyvinyl alcohol) is then dissolved in water until homogenous and then sieved through a sieve with a mesh size of 0.7mm and cooled to a temperature of no more than about 30"C. Bupropion hydrochloride is placed in the upper spray chamber of a fluidized bed apparatus, such as, for example, the Siai SRSS1 fluidized bed apparatus.

A soluble binder (i.e., a solution of polyvinyl alcohol) is sprayed onto bupropion hydrochloride with the technological parameters shown in Table 2:

Table 2

Granulation process parameters

Air flow (m3/h) 2000-2500 150-250 5020-70С

The outlet temperature is 3070-5070

Spray pressure (Bar)

Product temperature 3576-5070

After the end of granulation, the granules are allowed to dry and then cooled to a temperature of no more than about 35°C. The bupropion hydrochloride granules are then sieved through a sieve with a mesh size of 1.4 mm.

The lubricant (glyceryl behenate) together with the sieved granules is then mixed in an M-blender until the mixture is evenly mixed. The resulting mixture is pressed into tablet cores using a rotary tablet press (Mapeviu Opirge55) with an average hardness of about 8 scruples to about scruples and an average thickness of about 3.9mm to about 4.5mm for 150mg tablet cores and an average hardness of about 12 scruples to about 33 scruples and an average thickness of about 4.8 mm to about 5.4 mm for the cores of 300 mg tablets. The brittleness of tablet cores for both forms is no more than 0.895. The tablet cores are then coated with the release control coating formulations shown in

Tables 3:

Table C

The composition of the shell that controls the release of mg/9b1 Mg/9o mg/9o Mg/9o mg/9o mg/9o 10.26/5.55 | 5.63/3.1 12/6.28 19/5.01 6.71/1.96 | 13.05/3.63 film-forming polymer ОЙ 77771111 release, in the dry state 1 Indicators mg/95 represent the ratio of the ingredient to the weight of the tablet in the dry state 2 Ethylcellulose 100 (Eshtosef)

With Polyvinylpyrrolidone (KoiPdopF 90) 4 Polyethylene Glycol 1450 (Sagromahf))

Evaporation during drying

A plasticizer (polyethylene glycol 1450) and then a water-insoluble, water-permeable, film-forming polymer (ethylcellulose 100) are added to a portion of a mixture of denatured ethyl alcohol and isopropyl alcohol.

After mixing, the water-soluble polymer is gradually added to the above mixture to avoid large particles and lumps. The solution is mixed until homogeneous. The remainder of denatured ethyl alcohol and isopropyl alcohol is then added to the shell mixture and mixing is continued until a homogeneous solution is achieved. The casing mixture is then sieved through an OeWee Homogenizer (nozzle size 7, process pressure: 8500252000 psi and back pressure: 10002250 psi). The homogenized coating solution is then sprayed onto the tablet cores in a (tablet machine) coating machine (O'Naga 36 bide Mep) with the process parameters shown in Table 4:

Table 4

Technological parameters of application of the shell, which controls the release

Coating of the tablet cores with the release control coating solution is continued until a weight gain of about 24 mg (wet coating is about 22 to about 26 mg) and a weight gain of about 29 mg (wet coating is about 27 to about Zimg) are achieved for cores of 150mg and Zb0Omg tablets, respectively. After obtaining the specified weight gain, coating is stopped and the coated tablet cores are dried at an inlet air temperature of about 35-42"C with a drum speed of about 2 revolutions per minute. The dried and cooled coated tablet cores are then coated with a moisture-resistant coating composition as shown in Table 5:

Table 5

The composition of the moisture-resistant layer (m/o)! (mg/9o) (mg/9o) (mg/do) (mg/do) (mg/9o)

Combination of plasticizer (O-E)Z (0-0.46 (0-0.46 | (0-0.46 (0-11 (0-0.49 (0-0.69

E-0.23) E-0.23) | E-0.23) E-0.56) E-0.25) E-0.35) 0.69/0.38 | 0.69/0.38 | 0.69/0.36 | 1.66/0.44 | 0.74/0.21 | 1.04/0.29 1 Indicators mg/95 represent the ratio of the ingredient to the weight of the tablet in the dry state 2 poly(methacrylic acid, methyl methacrylate) 1:1 (Eidgadikuyu I 30 0-55) with rePolyethylene Glycol 1450 (SagrozhakhF)), Ex: Triethyl Citrate 4 Silicon dioxide (ZuioidF 244) from Evaporation during drying

A combination of plasticizer, preferably polyethylene glycol 1450 and triethyl citrate, is first dissolved in a portion of purified water and mixed until homogenous. During mixing of the plasticizer solution, a copolymer of methacrylic acid, preferably Etsagadikyu I 30 0-55, is sifted through a sieve with a mesh size of 0.Zmm in a separate container . The plasticizer solution is then added to the methacrylic acid copolymer and mixed until a homogeneous solution is achieved. During mixing of the methacrylic acid copolymer/plasticizer solution, a penetration enhancer, preferably silicon dioxide, is dissolved in the residual water and mixed with a high shear stirrer until the slurry is homogeneous. The final solution of the moisture-resistant layer is obtained by mixing the penetration enhancer solution with the methacrylic acid copolymer/plasticizer mixture. The homogenized moisture-resistant layer solution is then sprayed onto the release-controlling coating-coated tablet cores in a coating drum with the process parameters shown in Table 6:

Table 6

Technological parameters of applying a moisture-resistant layer

Drum speed (rpm) 5-15 5-15

Outlet temperature ("C)) 25-40 25-40

Temperature at the entrance (C) 30-60 30-60

Sawing speed (g/min) 160-400 160-400

Atomizing Air Pressure (psi) 30-50 30-50 in.

Model Air Pressure (psi) 20-40 20-40

Airflow (cubic feet per minute 8000-1100 8000-1100

The moisture-resistant layer is applied until a weight gain of about 7 mg (wet tablet shell is about 6.3 to about 7.7 mg) and about 10.5 mg (wet tablet shell is about 9.5 to about 11, 5 mg) for 150 mg and 30 mg modified-release tablets, respectively. After obtaining the specified weight gain, the application of the coating is stopped, and the coated tablets are dried at an inlet air temperature of about 3542"C with a drum speed of about 2 revolutions per minute.

The coated tablets are finally imprinted with the appropriate markings using a suitable black ink such as OrasodeF 5-1-8090 black ink using a tablet printer (Riipi Ipiegpaiiopai)!).

The dissolution profile for each of the three 150mg and 300mg forms was determined under the following dissolution conditions:

Medium: 900ml, 0.1M NSI

Method: Device of the US Pharmacopoeia Type I (150 mg dose) / Device of the US Pharmacopoeia

Type II (ZOOmg dose), at 75 revolutions per minute and 377

The results presented in Table 7 show the average percent release of the total bupropion hydrochloride content of the coated tablets:

Table 7 in GG with | And | in her with | A / (0) (0) (0) (0) (0) (0) (0) 1 1.7 0.1 0.3 15 1 0.15 2 21.2 4.2 6.4 33 9.5 3.5

From 40.6 19.5 17.5 48.5 23.5 11.5 4 56.2 351 28.7 62.5 36.5 20 69.2 49 1 92.6 84.6 98 87 69.5 11 98 95.1 89.7 99 90.5 76.5 12 98.7 96.7 92.7 92.7 99.5 93.5 82.5 97.6 100.5 98 96.5 100.5 99 97 101 99 97.5 101 99 98.5 101 100 98.5

101 100 99 101 99.5 99.5 101 100 99.5

The average dissolution profile for three different 150 mg and 300 mg modified release bupropion hydrochloride tablets is shown in Figures 1A and 18, respectively.

Formulations C and C for dosage forms of 150mg and 30mg were selected for further tests and production. 2. Stability of compositions of tablets with modified release.

These compositions do not contain a stabilizer. To determine the stability of bupropion hydrochloride in the absence of a stabilizer, stability tests were carried out under accelerated conditions for 6 months at a temperature of 40"Сх2"С/relative humidity 75902590 and under long-term conditions for 12 and 18 months at a temperature of 25"Сх2"С/ and relative humidity 6095 and 595. After the expiration date, the tablets were analyzed for impurities resulting from the breakdown of bupropion hydrochloride after high-performance liquid chromatography. Decomposition products included those listed in the US Pharmacopoeia (26th edition, page 281) and any other peaks that appeared on the chronograph.

Results of stability tests under accelerated and long-term conditions for dosage forms of 150 mg and

ZbOmg are shown in Tables 8, 9 and 10:

Table 8

Accelerated conditions (temperature 40"C2"C/relative humidity 7525905)

General General General General impurities impurities impurities impurities 1 0.67 o 63 0.93 0.63 0.7 0.50 0.57 0.63

C 0.6 0.80 0.8 o 86 0.7 0.70 0.67 0.84 b 1.0 1.09 1.0 1.22 1.0 0.98 0.9 1.20 1 Moisture and impurity indicators are the average of three batches 2 Moisture content according to the Karl-Fisher method (95)

C Total impurities obtained from bupropion hydrochloride, which decomposed as 95 bupropion hydrochloride present from the beginning of the analysis

Table 9 12 months of aging under stable conditions (temperature 25"Сж2"С/relative humidity 60952590) 11111111 | Acceptable tolerances Derived data | Amount in tablets for 12 months

Table 10 18 months of aging under stable conditions (temperature 25"Са2"С/relative humidity 6095590) 11111111 | Acceptable tolerances Derived data | Amount in tablets for 18 months

The 48-month stability data were evaluated using a statistical analysis of the expiration date for each modified-release tablet dosage form. Expiration curves are presented in Fig. 2A and 28. Specifications "based on the data" were derived by estimating the level of the upper confidence interval predicted for 48 months.

Example 2 1. The moisture-resistant layer is not an enteric coating.

The purpose of the study was to show that buproton hydrochloride tablets, according to the present invention, are not coated with an enteric coating. The modified-release formulation is based on a tablet core consisting of bupropion hydrochloride, a binder, and a lubricant. The tablet core is coated with a release-controlling coating, the function of which is to control the release of bupropion hydrochloride.

The tablet cores, coated with a release-controlling coating, are then coated with a moisture-resistant layer that substantially prevents or delays the absorption of moisture.

Drug release was measured spectrophotometrically using a two-stage dissolution procedure using the US Pharmacopoeia Method B, which defines the dissolution conditions of the enteric coating (in a drum at 75 revolutions per minute), to assess tablet integrity. The test results are shown in Tables 11 and 12:

Table 11

Release time and deviation value (0) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0 0.0 0.6 0.5 1.2 0.2 0.3 0.7 2 FOR 1.7 9.7 7.3 10.2 7.2 6.5 3.5

Table 12

Release time (hours) Average Standard 1 21.8 20.3 19.2 21.2 21.6 20.3 20.7 1.0 2 35.2 34.6 32.4 34.9 33.9 32.9 34.0 11

З 45.0 45.1 43.3 45.5 42.8 43.5 44.2 1.2 4 53.2 55.0 51 53.1 50.6 51.2 52.3 1.7 59.6 64.6 57.2 59.5 58.0 57.4 59.4 2.8 б 64.7 70.7 62.2 65.1 66.7 62.7 65.3 34 7 69.1 75.1 66.6 69.4 71.7 67.1 69.8 3.2 8 74.4 78.1 70.1 73.0 75.8 71.8 73.9 2.9 9 78.8 80.1 73.2 75.8 77.6 75.7 76.9 2.5 81.6 81.5 75.5 77.7 78.6 77.8 78.8 2.4 11 83.2 82.5 77.2 79.3 79.5 7941 80.1 2.3 12 841 83.1 78.0 80.6 80.0 79.9 81.0 2.3 13 84.6 83.7 78.4 81.3 80.2 80.4 81.4 2.3 14 84.9 84.0 78.6 81.5 80.2 80.8 81.7 2.4

At an acidic pH (0.1 M NOSI), about 795 bupropion hydrochloride is released within 2 hours, but at a pH of 8, about 2195 bupropion hydrochloride is released within 1 hour. Thus, the modified-release tablet according to the present invention does not meet the requirements of the US Pharmacopoeia for an enteric-coated tablet, i.e. after 2 hours in an acidic medium (0.1 M HCl), no individual indicators should exceed 1095 of the dissolved active drug and not less , than 7595 must be dissolved within 45 minutes in buffer rinb.8.

The functionality of the moisture-resistant layer as a non-enteric coating was further demonstrated by directly applying 150 mg tablets of the moisture-resistant layer to the cores. Table 13 shows that the dissolution results (first 2 hours in an acidic medium) do not meet the requirements of the US Pharmacopoeia for an enteric-coated tablet.

Medium: 900ml, 0.1M NS

Method: USP Type I Apparatus at 75 rpm and 377

Table 13

Deviation deviation value time, 95 (0) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 45.6 | 41.7 | 39.8 | 46.5 | 42.4 | 501 44.3 3.8 8.5 2 75.5 | 73.7 | 69.1 76.4 | 71.3 | 84.6 75.1 5.4 7.2

From 93.9 | 98.4 | 95.1 93.4 | 89.4 | 100.9 95.2 4.0 4.2 4 99.1 99.1 | 102.2) 102.0) 99.0 | 102.5 100.6 1.7 1.7 5 99.5 | 99.1 102.2 | 103.5 | 101.7 | 102.5 101.4 1.8 1.7

Testing in buffer solution was not performed due to high release in acidic medium. 2. The moisture-resistant layer performs the function of significantly preventing or delaying the absorption of moisture.

The functionality of the moisture-resistant layer as a coating that significantly prevents or delays the absorption of moisture was confirmed by determining the moisture content by the Karl-Fisher method in both the tablet cores coated with the release control coating and in the tablet cores coated with the moisture-resistant layer for the 300mg tablet cores. The preparation of the compositions is described in Example 1. The corresponding coated tablets were placed separately under accelerated conditions (at a temperature of 40"C2"C/relative humidity 75902590) in an open glass cup for 10 days.

As shown in Table 14, the moisture content of the tablet cores coated with a release control coating is higher than that of the tablet cores coated with a moisture resistant layer.

Table 14

Moisture content according to the Karl-Fisher method, 90 with a layer of 0.45

The data presented in Tables 13 and 14 demonstrate that the moisture resistant layer does not function as an enteric coating as defined by the US Pharmacopoeia. Rather, these data demonstrate the functionality of the moisture-resistant layer as a shell that significantly prevents or delays moisture absorption.

Example C

The purpose of this study was to determine the equivalence of dosage forms using the following test for 150mg and 300mg bupropion hydrochloride modified-release tablets under fasting conditions. A two-way, cross-over, open-label, single-dose, fasting equivalency study of the efficacy of dosage forms (150 mg and 30 mg) of modified-release bupropion hydrochloride tablets according to the present invention was conducted. The modified-release tablets of the present invention were administered once daily to normal, healthy, non-smoking male and female subjects.

The study design included a two-term, double-treatment, single-dose, and fasting design. The study periods were separated by a three-week washout period. A total of 36 people (19 men and 17 women) agreed to participate in the study, of which 35 people (19 men and 16 women) completed the study. The subjects who were studied were prescribed the following treatment:

A) 2 x 150 mg tablets of bupropion hydrochloride with modified release to be taken once a day, according to the present invention, were administered orally with 240 ml of water at room temperature, after which an overnight fast was prescribed for at least 10 hours.

C) 1x300 mg tablet of bupropion hydrochloride with a modified release to be taken once a day, in accordance with the present invention, was administered orally with 240 ml of water at room temperature, after which an overnight fast was prescribed for at least 10 hours.

Graphical profiles of the average plasma concentration (ng/ml) of bupropion and its metabolites: hydroxybupropion, bupropion of threoamino alcohol and erythroamino alcohol during 120 hours after taking the following dosage forms: 2x150mg once a day and 1x30mg once a day are shown in Fig. ZA -Y, respectively.

Tables 15a-4 present the mean (standard deviation) pharmacokinetic data for bupropion following administration of 2 x 150mg tablets once daily or 30mg tablets once daily:

Table 15a (Bupropion) 2x150mg bupropion NS tablets | 1x30mg bupropion NSI tablet 1

Pharmacokinetic parameter (mean 2 with modified with modified release, values standard deviation) release, according to according to the present invention, this invention, (n-35 n-35

AiMsoch (ng-"h /ml) 1648.85:2475.34 1676.613474.09

AMso-tp (ngoh / ml) 1702.692489.30 1728.343478.43

Stakh (ng/ml) 150.11537.22 146.88:547.61

Ttah (HOURS) 4.9950.76 5.20520.88

She (hours) 22.1057.42 21.84 7.35

Kei (hour) 0.03650.017 0.037-0.018

MAT (teap hesomegu (ite)

Average recovery time) (hours 22.2855.50 22.9255.50

Table 15r (Hydroxybupropion) 2x15O0mg tablets of bupropion NSI n xZz0Omg tablet of bupropion NSI 1

Pharmacokinetic parameter (mean 2 with modified with modified release, values standard deviation) release, according to according to the present invention, the present invention, (n-35 n-Z35

ASHMsoch (ng'h /ml) 22506.3459372.50 22380.3218740.47

AMso-tp (ngoh /ml) 23634.19210373.91 23498.8159584.58

Stakh (ng/ml) 492.97-4182.28 479.2352172.64

Ttah (HOURS) 11.665.64 14.0625.10

She (hours) 24.0124.85 24.0954.57

Kei (hour") 0.030-0.007 0.030-0.006

MAT (teap hesomegu (ite) (Average recovery time) (hours) 39.93276.94 41.18527.07

M/R ratio 13.488655.3391 13.296625.0489

Table 15 p

(Bupropion treoamino alcohol) 2x150mg tablets bupropion NOSI xZ0Omg tablet bupropion NSI 1 with

Pharmacokinetic parameter (mean 2 with modified modified release, values standard deviation) release, according to according to the present invention, the present invention, (p:35) p-Z35

AiMsoch (ng-"h /ml) 7548.0553627.79 7262.8853083.24

AMso-tp (ngoh / ml) 9428.7314982.30 9091.33253926.24

Stakh (ng/ml) 173.22160.80 162.24558.97

Ttah (HOURS) 7.1612.65 8.475341

Hours (hours) 50.4716.76 51.51216.83

Kei (hour") 0.01520.005 0.015:0.005

MAT (teap hesomegu (ite) (Average recovery time) (hours) 69.31222.44 71.33221.93

M/R grove 5.437852.1088 5.277452.0478

Table 154 (Bupropion erythroamino alcohol) 2x150mg tablets bupropion NSI | 1x30mg bupropion tablet NSI

Pharmacokinetic parameter (average | 2 with sustained release, | 1 with sustained release, values standard deviation) according to the present invention, according to the present invention, p-Z35 p-Z35

AiMsoch (ng-"h /ml) 1508.79-601.87 1441.85:495.53

AMso-tp (ngoh / ml) 1702.715777.29 1613.65-4623.69

Stakh (ng/ml) 28.8826.54 27.5216.67

Ttah (HOURS) 13.0323.48 15.2434.15

She (hours) 32.1528.65 32.1259.22

Kei (hour") 0.02320.007 0.02320.006

MAT (teap hesomegu (ite) (Average recovery time) (hours) 51.605212.65 52.34 513.44

M/R grove 0.9985:20.3678 0.952770.3863

The results of the relative bioavailability analysis (2 x 150 mg (daily) compared to 1 x 300 mg (daily)) for

AMsSo-p, AOSoi, and Stach, transformed using the natural logarithm of the fasting state, collected in

Tables 16 for bupropion and its metabolites:

Table 16

Bimisnyk shchyk Ky NIe S 909 S. medium subject 9090 S.I. medium subject geometric | coefficient of variation of geometric | coefficient of variation 102.769o 98.269o 11.0795 106.07 100.089o 14.53790

AMsSocht 93.97 - 942396 - 102.8890 98.329o 11.1995 105.8190 99.859o 14.3295

Stakh 97.77 - 97.76 - 110.309o 103.849o 14.9095 108.179o 102.8490 12.5195

Mice and i Y 9095 S.I. average subject 9095 S.I. medium subject geometric | coefficient of variation of geometric | coefficient of variation 109.169o 102.72 15.0395 110.309o 103.349o 16.0995

AMsSocht 94.8796 - 97.09 - 108.579о 101.4995 16.6695 110.8995 103.76 16.4295

Stakh 100.0695 - 99.4195 - 114.0395 106.8290 16.1695 111.2695 105.17 13.9195

The data show that both dosage forms - 150 mg twice daily dose and 300 mg once daily dose - of the modified-release tablets according to the present invention, which are described in Example 1, are equivalent to each other with respect to their pharmacokinetic parameters for bupropion and its metabolites.

Example 4

A four-way, crossover, open-label, single-dose, fasted, and meal-effect study comparing the bioavailability of 150 mg bupropion hydrochloride modified-release tablets as described herein and in Example 1 to 7urapF 150 mg tablets was conducted in which normal, healthy, non-smoking, female and male subjects. This study was designed to evaluate the rate and extent of postprandial and fasting bupropion absorption following administration of 150 mg bupropion hydrochloride modified-release tablets as described in Example 1.

In parallel, this study also evaluated the rate and extent of absorption of bupropion after meals and on an empty stomach after taking 150 mg tablets 2urapf)

The study design included a two-time, double-treatment, single-dose, fasted, and postprandial crossover design. The study periods were separated by a two-week washout period.

A total of 35 individuals (24 men and 11 women) agreed to participate in the study, of which 32 individuals (22 men and 10 women) completed the study. The subjects who were studied were prescribed the following treatment:

A) 150 mg daily bupropion hydrochloride tablets with modified release, according to the present invention, on an empty stomach,

C) 150 mg of modified-release bupropion hydrochloride tablets daily, according to the present invention, after meals,

C) 150 mg daily tablets 2urapb on an empty stomach, and

O) 150 mg daily 7urapf tablets after meals.

Graphical profiles of the mean plasma concentration (ng/ml) of bupropion and its metabolites: hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol 72 hours after taking 1 x 150 mg once a day of modified-release bupropion hydrochloride tablets according to the present invention, and 1 x 150 mg single once a day tablets 7urapF, shown in Fig. 4A-E.

Table 17 presents the mean (and standard deviation) pharmacokinetic data for bupropion after administration of 150 mg modified-release tablets according to the present invention or commercially available 72urapF prototype tablets in the fasted and post-meal state for bupropion and its metabolites:

Table 17

Arithmetic mean: standard deviation (95 coefficient of variation)

NSI bupropion tablets

Pharmacokinetic | Tablets bupropion NSI with modified

What is the release of 150mg according to this (Fasting heart) (p-:32) (After meal) (p-32) (Fasting heart) (p-32) | invention, 150mg (After meal) (p-:32) 864.56-4259.86 918.59 z2271.21 881.484-270.64 1048.50-306.63 30.06 29.52 30.70 29.24

AMsSochi (ng"h/ml) 886.16227 926.4870" 8842148" 1043.88027

Бона: ШИ ШИ ШИ 28.48 30.02 31.32 29.85 81.78524.47 75.755-19.77 96.965231.38 128.812532.03 29.93 26.10 32.37 24.87 22.02 33.10 25.41 25.99 (34.97) (35.15) (29.75) (27.99) (41.996) (42.214) (42.096) (38.386) 49.43 57.81 47.93 46.08 12611.91-8151.69 12604.70-7739.11 12976.49-6817.46 14679.97-8184.51 (64.63) (61.40) (52.54) (55.75) 13034.17 5820741 13049.554-7933.08 13344.28-6863.47 15129.56-48370.60 (62.97) (60.79) (51.43 ) (55.33)

Stakh (ng/ml) 2222716 230.4191 294.8008 301.9918 Mish: Shi nn JN 48.83 44.73 39.73 40.42 (40.32) (28.31) (19.56) (40.5.49) 23.42

ASHMsoch (ng"h/ml) 4223.4179 4397.5375 4376.0423 5042.7155

Milne: Dreams DREAMS OF BLUE 58.39 64.98 55.29 49.18 5006.42-3088.85 5360.0023691.31 5147.80-42897.63 5853.8543083.187 61.70 68.87 56.29 52.67

88.4337.68 93.97-36.82 112.12234.64 130.6540.68 42.61 39.18 30.90 31.13 (36.12) (28.39) (17.65) (17.66) (30.10) (30.22) (27.34) (28.05) 30.287 30.636 265.839 31.030 82.07 75.49 75.11 76.92 675.245321. 49 722.155341.87 716.66-300.64 823.245320.87 (47.81) (47.30) (41.95) (38.98) 768.155333.66 816.355372.52 802.32315.77 893.6525330.207 (43.44) (45.63) (39.36) (36.95) 14.1753.85 15.0423 ...

The results of the analysis of relative (modified-release tablets according to the present invention, fasting and after food) bioavailability for ASHSop, AOSoi, and Stakh, transformed using the natural logarithm under conditions of fasting and after food, are collected in Table 18 for bupropion and its metabolites:

Table 18 o. Internally - o. Within-mean n children mean n children coefficient of variation coefficient of variation

AOSol Mov 10685296 11.78696 tota, 102.27596 16.97196

AOSocht ek 104.78896 10.53396 ovo 101.99396 1584496

Stakh nn 93.10795 1747095 en 104.04395 16.33695 9096 S.I. average subject 9096 S.I. medium subject geometric | coefficient of variation of geometric | coefficient of variation

AOSoi to lav, 10410895 12.64695 Mov 107.78095 15.56495

AOSochy Mn 105.27495 12.26995 about 106.13295 1312795

Stakh Mch 106.88495 1499895 Moon 106.71295 12.66295

The data in Table 10 show that the bioequivalence of bupropion and its metabolites does not show the effect of food, that is, the modified-release tablets according to the present invention, which contain bupropion hydrochloride, are bioequivalent in the presence or absence of food, which is confirmed by the fact that the 9095 SI ratio geometric means for AOsSo-i, (and AOSo-i, where appropriate), and Stakh, when taken on an empty stomach in relation to taking after a meal, correspond to the limits of 80-12595 proposed by the Federal Drug Administration.

Example 5

A two-way, cross-over, open-label, single-dose, food-fed study of the relative bioavailability of 300 mg modified-release bupropion hydrochloride tablets according to the present invention was conducted in normal, healthy, non-smoking, female and male subjects. sex

This study was designed to evaluate the effect of food on the rate and extent of absorption of 300 mg bupropion hydrochloride modified-release tablets for once-daily administration, in accordance with the present invention, under single-dose conditions. The study design included a cross-sectional design with two terms,

double treatment, single dose, on an empty stomach and after a meal. The study periods were separated by a two-week washout period. A total of 36 individuals (26 men and 10 women) agreed to participate in the study, of which 32 individuals (23 men and 9 women) completed the study. The subjects who were studied were prescribed the following treatment:

A) 1x300Omg tablet with modified release after 10 hours of fasting.

C) their 300 mg modified-release tablet after a full breakfast with a high fat content.

Graphical profiles of the mean plasma concentration (ng/ml) of bupropion and its metabolites: hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol 120 hours after taking 1xZzb0Omg once a day of a tablet of bupropion hydrochloride with a modified release, according to the present invention, on an empty stomach and after a meal are shown in Fig. 5A-O, respectively.

Table 19 presents the mean (x standard deviation) pharmacokinetic data for bupropion and its metabolites after administration of 300 mg modified-release tablets according to the present invention, fasted and after meals:

Table 19

Bupropion NSI tablets with Bupropion NSI tablets with modified

Pharmacokinetic modified release of Z0Omg |release of ZbOmg (Fasting heart) (p-31) parameter (After food) (p-31) Average values Average values Standard

Standard Deviation Deviation 11111111 Bupropone///://///SSSSSSSSSS

ASHMsoch (ng'h /ml) 1775.455530.77 1628.3825511.15

AMso-tp (ngoh / ml) 1832.542548.50 1678.3625521.18

Stakh (ng/ml) 138.36242.35 151.352448.87

Ttah (HOURS) 6.16:21.84 5.16.0.86

She (hours) 21.7655.85 21.2116.17

Kei (hour) 0.035:0.011 0.03650.012

MAT (hour 22.564.60 21.58:4.23

AiMsoch (ng-"h /ml) 19733.51259411.52 18938.8458387.21

AMso-tp (ngoh / ml) 20886.13210230.69 19852.7329049.54

Stakh (ng/ml) 449.05:2181.73 409.795154.84

Ttah (HOURS) 14.3253.18 13.7155.15

Wed (hours) 24.1155.21 23.95:24.84

Kei (hour") 0.03050.007 0.030-0.007

MAT (hour) 42.037.60 41.08526.13

M/R Rayo 10.591953.8325 11.317854.6281 00101110 Bupropiontrevamin alcohol/// | 77777771

AiMsoch (ng-"h /ml) 9769.6926136.11 9032.19-46595.77

AMso-tp (ngoh /ml) 13280.57259398.23 11696.2929018.00

Stakh (ng/ml) 208.39298.15 182.5299.62

Ttah (HOURS) 12.26:53.36 9.945484

Hours (hours) 55.095217.66 55.25120.72

Kei (hour") 0.014320.004 0.014-0.004

MAT (hour) 79.10325.10 78.60328.28

M/R Rayo 6.943553.8129 6.641723.4215

AiMsoch (ng-"h / ml) 1803.4525693.19 1634.562-741.60

AMso-tp (ngoh /ml) 2116.01-51026.23 1867.742971.96

Stakh (ng/ml) 35.8029.13 31.0329.97

Ttah (HOURS) 14.7452.71 14.16253.85

Hours (hours) 35.23212.03 33.89311.02

Kei (hour) 0.0210.006 0.022:20.006

MAT (hour) 57.78217.49 54.753214.45

M/R Rayo 1.132210.3876 1.0947-0.3952

The results of the analysis of the relative (when taken after a meal compared to when taken on an empty stomach) bioavailability for AsCo-p, ACo-, and Stach, transformed using the natural logarithm under fasting and post-meal conditions for bupropion and its metabolites, are collected in Table 20:

Table 20 ishsyay shchyk IN VSYY 9095 S.I. average subject 9095 S.I. average subject geometric |coefficient of variation geometric |coefficient of variation

AMOSochi )104.1895-116.4995 110.1695 12.9395 97.0396-112.7290 1045890 17.35960

Stakh 84.4995-100.869o 92.319o 20.509o 103.4496- 109.97 14.1795

116.9195 breath and MOUSE and 9095 S.I. average subject 9095 S.I. average subject geometric |coefficient of variation geometric |coefficient of variation

AshsSol 104.3195-121.1895 112.4295 17.3695 104.0695- 113.3990 19.89965 123.5690 126.6195

Stakh 110.6195-124.9695 117.5790 141295 110.14965- 117.9995 15.9495 126.409o

The data in Table 20 show that the bioequivalence of bupropion and its metabolites from 30 mg of modified-release bupropion hydrochloride tablets according to the present invention does not show the influence of food, which is confirmed by the fact that the 9095 CI ratio of the geometric means for ASHsSoch-p, (and AOSo -, where appropriate), and Stakh when taken on an empty stomach, in relation to taking after a meal, correspond to the limits proposed by the Federal Drug Administration in 80-12595.

Example 6

A two-way, crossover, steady-state, multiple-dose, open-label, fasted, comparative bioavailability study of 300 mg bupropion hydrochloride modified-release tablets, according to the present invention, was conducted in comparison with 100 mg immediate-release tablets of Bupropion Hydrochloride administered three times, in in which normal, healthy, non-smoking, female and male subjects participated. This study was planned to evaluate the bioavailability of ZOOmg modified-release tablets according to the present invention, compared to the available on the market UmePriyipF immediate-release prototype tablets with three-time intake in a stationary state and on an empty stomach.

The study design included a two-term, double-treatment, step-up, multiple-dose, and fasting design. A total of 40 people (27 men, 13 women) agreed to participate in the study, of which 30 people (22 men, 8 women) completed the study.

The subjects who were studied were prescribed the following treatment:

A) 100mg MeiPriigipe tablets were administered orally at 0.0 hours (starting at 7:00 am) on days 1.2 and 3 (twice daily) with 240 ml of room temperature water after an overnight fast of at least 10 hours. All subjects also received a second dose of 1 100 mg tablet (U/ePrinipF) at 12.0 hours with 240 ml of room temperature water after fasting for at least 1 hour. On days 4-13, subjects received a 30 mg tablet of modified-release bupropion hydrochloride according to the present invention at 0.0 hours (starting at 7:00 a.m.) with 240 ml of room temperature water after an overnight fast of at least 10 hours.

C) 100 mg tablets of U/ePriipF were administered orally at 0.0 hours (starting at 7:00 am) on days 1, 2 and 3 (twice daily) with 240 ml of room temperature water after an overnight fast of at least 10 hours. All subjects also received a second dose, which consisted of 1 100 mg tablet of UUePiriNipF), at 12.0 hours with 240 ml of room temperature water after fasting for at least 1 hour. On days 4-13, subjects received 1 100 mg tablet of U/eiriipF at 0.0 hours (starting at 7:00 AM) with 240 mL of room temperature water after an overnight fast of at least 10 hours. All subjects then received a second dose of 1 100 mg U/eirshipF tablet at 6.0 hours with 240 ml of room temperature water after fasting for at least 71 hours. All subjects then received a third dose consisting of 1 100 mg tablet of U/ePrSnPF at 12.0 hours with 240 ml of room temperature water after fasting for at least 1 hour.

Graphical profiles of the average plasma concentration (ng/ml) of bupropion and its metabolites: hydroxybupropion, bupropion of threoamino alcohol and erythroamino alcohol after the end of the study period after taking 1 x 300 mg once a day of modified-release tablets according to the present invention and Хх 100 mg tablets U/eiIPriiipF are shown in Fig.bA-E, respectively.

Table 21 presents the average (and standard deviation) pharmacokinetic data for bupropion after once-daily administration of 300 mg modified-release tablets according to the present invention, or three times a day of the commercially available 100 mg prototype U/ePriipF tablet):

Table 21. - ZbOmg tablets bupropion NSI with modified 100mg tablets uveprinipe

Pharmacokinetic : : : sh (p-30) release, according to the present invention, (p-30) parameter (Average values Standard deviation) (Average values

standard deviation)

AIMsSoch, (ng"h/ml) 1612.042490.27 1791.982483.43

Stakh (ng/ml) 167.50246.56 175.40-56.03

Stip (ng/ml) 27.64210.73 34.0612.49

Ttah (HOURS) 4.9020.89 1.6020.58

Degree of fluctuation (9) 212.56539.42 189.98238.99

Exactly (ng/ml) 67.17520.43 74.67520.14

Degree of oscillation (95) 554.5952193.21 439.582-141.64

M/R grove 12.925.31 12.6155.11

AIMsSoch, (ng'h/ml) 20824.7757423.56 22456.08-6889.20

Stakh (ng/ml) 1095.64-385.06 1156.34 339.34

Stip (ng/ml) 122.235281.76 800.905262.97

Ttah (HOURS) 7.301245 2.4750.83

Degree of fluctuation (9) 44.34216.57 40.782531.24

Exactly (ng/ml) 867.705309.32 935.675287.05

Degree of oscillation (95) 54.65122.48 49.19240.60

M/R gayo 7.0151.84 6.9151.81

AIMsSoch, (ng'h/ml) 10987.8823193.09 12051.4253107.48

Stakh (ng/ml) 585.362155.83 629.81-138.84

Stip (ng/ml) 364.4212122.60 415.71-4122.32

Ttah (HOURS) 7.831215 2.49:50.81

Degree of fluctuation (9) 50.47317.22 45.25121.80

Exactly (ng/ml) 457.835133.05 502.14-129.48

Degree of oscillation (95) 65.68226.11 56.34 529.48

M/R gayo 1.39520.44 1.360.43 11111111 Bupropionerythramine alcohol/:////::

AIMsSoch, (ng'h/ml) 2145.70-615.22 2353.735645.40

Stakh (ng/ml) 109.07-29.98 119.37-26.82

Stip (ng/ml) 76.51-25.69 85.59226.63

Ttah (HOURS) 8.3742.04 2.400.66

Degree of fluctuation (9) 38.11215.25 38.90533.91

Exactly (ng/ml) 89.40125.63 98.07526.89

Oscillation degree (95) 46.04520.70 46.18243.72

M/R gayo 1.39520.44 1.360.43

The results of the analysis of the relative (tablets with a modified release, according to the present invention, in comparison with UmeiPrshihipF) bioavailability for APSoi, and Stakh for bupropion and its metabolites, transformed using the natural logarithm, are summarized in Table 22:

Table 22 of mean number of children mean number of children coefficient of variation coefficient of variation

Stakh 91.0875-103.0095 96.869o 13.9795 85.980-99.9090 92.689o 17.0496 average children average children coefficient of variation coefficient of variation

Stakh 87.42905-97.2890 922250 121395 84.8496-95.8990 90.20 13.9195

The data in Tables 21 and 22 show that the 300 mg modified release tablet of the present invention, administered once daily, is bioequivalent to the 100 mg UmePriigipF immediate release tablet administered three times daily.

Example 7

A two-way, cross-over, open-label, multiple-dose, fasting, comparative study of the bioavailability of 30 mg modified-release bupropion hydrochloride tablets according to the present invention was conducted in comparison with commercially available 150 mg prototype 7urapF tablets in normal, healthy subjects. non-smokers, female and male. This study was designed to compare the bioavailability of 300mg bupropion hydrochloride modified-release tablets for once-daily administration, according to the present invention, with the commercially available 150mg prototype 7urapF twice-daily tablets.

The study design included a two-term, double-treatment, multiple-dose, and fasting design. The study periods were separated by a two-week washout period. A total of 54 people (40 men and 14 women) agreed to participate in the study, of which 49 people (37 men and 12 women) completed the study. Subjects who were studied were prescribed daily 150 mg tablets of 7urapFf starting from days 1-3 of this study. After 4-17 days:

A) 300mg tablets of bupropion hydrochloride with modified release, according to the present invention, daily.

C) 150 mg tablets 2ubrapf twice a day.

Graphical profiles of the average plasma concentration (ng/ml) of bupropion and its metabolites: hydroxybupropion, bupropion threoamino alcohol and erythroamino alcohol after the end of the study period after taking 1x300mg once a day of modified-release tablets according to the present invention, and 2x150mg twice a day tablets 2urapF), fasting are shown in Fig. 7A-E, respectively.

Table 23 presents the average (and standard deviation) pharmacokinetic data for bupropion after taking once a day 300 mg of a modified-release tablet according to the present invention, or twice a day of a commercially available 150 mg tablet-prototype 2urapf:

Table 23

Pharmacokinetic (arithmetic average o coefficient of variation) parameter of 300mg bupropion NOI tablets with modified 150mg tablets 7urape release, according to the present invention n--49 (n-49)

AMsSoch, (ng'h/ml) 1412.4767 1561.9651 1464.21(28.12) 1617.72(26.94)

Stakh (ng/ml) 143.9693 135.9517 148.81(26.10) 141.65(28.36)

Stip (ng/ml) 23.1224 25.3277 24.50(35.46) 26.85(35.28)

Ttah (HOURS)" 4.92(17.03) 3.23(31.63)

Degree of fluctuation (95)" 207.65(20.47) 171.85(19.27)

Degree of oscillation (90)" 551.15(37.98) 449.59(26.79)

Same (ng/ml)" 61.01(28.12) 67.41(26.94)

MAT (hours)" 9.63(6.57 10.23(2.90

AMsSoch, (ng'h/ml) 19688.697 21984.655 21255.88(38.44) 23792.58(39.17)

Stakh (ng/ml) 1035.5625 1114.0976 1111.28(36.14) 1200.37(38.41)

Stip (ng/ml) 669.3453 775.6489 731.59(41.72) 847.91(42.12)

Ttah (HOURS)" 6.61(34.52) 4.26(35.36)

Degree of fluctuation (95) 44.42(35.50) 36.96(50.36)

Degree of oscillation (905)" 56.7 7(47.41) 46.22(75.49)

Same (ng/ml)" 885.66(38.44) 991.36(39.17)

MAT (hours)" 11.43(2.87) 11.53(1.93)

M/R Raiyo" 14.538(43.310 14.684(43.323

AMsSoch, (ng'h/ml) 9040.7734 10398.325 9638.64(37.34) 11100.02(38.42)

Stakh (ng/ml) 494.6250 542.8864 524.91(37.35) 582.74(44.35)

Stip (ng/ml) 285.9451 339.2713 311.93(43.69) 370.23(45.18)

Ttah (HOURS)" 7.74(35.60) 4.45(35.77)

Degree of fluctuation (95)" 55.31(32.09) 47.19(32.50)

Degree of oscillation (905)" 75.80(43.62) 61.76(40.19)

Same (ng/ml)" 401.61(37.34) 462.50(38.42)

MAT (hours)" 11.63(2.85) 11.74(1.76)

M/R Raiyo" 6.609(29.472 6.830(26.491

AMsSoch, (ng'h/ml) 1784.5115 2033.8788 1875.33(31.95) 2125.14(30.18)

Stakh (ng/ml) 92.4622 101.5651 97.12(32.17) 105.63(28.49)

Stip (ng/ml) 61.3442 71.6863 65.30(36.05) 75.83(34.19)

Ttah (HOURS)" 8.31(38.42) 4.74(42.77)

Degree of fluctuation (95)" 41.87(43.18) 35.10(37.78)

Degree of oscillation (90)" 53.00(54.46) 43.04(50.13)

Same (ng/ml)" 78.14(31.95) 88.15(30.18)

MAT (hours)" 11.73(2.63) 11.73(1.87)

M/R Rayo" 1.298(27.168 1.334(25.504 x Expressed as arithmetic means (95 coefficient of variation)

The results of the analysis of relative (tablets with modified release, according to the present invention, in comparison with 2urapf)) bioavailability for AOSo-pi, AOSo-, and Stakh, transformed using the natural logarithm for bupropion and its metabolites, are collected in Table 24:

Table 24

Singing Internally. INTERNAL CORRELATION ' - Correlation ' - 9096 S.I. of medium subjects 9096 S.I. mean subject geometric coefficient geometric coefficient of variation variation

Stakh 99.2590-113.4695 106.1296 19.7390 89.0295-97.009о 92.9390 12.6695

Stipe 85.7 790-97.009o 91.2195 18.1495 82.220-90.349o 86.19 13.8895

Correlation Internal- Correlation Internal-

Parameter 9096 C. se - subject 9096 C - subject o 0.1. rednih g. about O.I. mean m geometric coefficient geometric coefficient of variation variation

Stakh 86.7675-95.789o 91.1695 14.59965 86.9575-95.449o 91.1095 13.7390

Stipe 80.45905-88.169o 8422950 13.4995 81.6175-89.609o 85.5195 13.7790

The data in Tables 23 and 24 show that a 300 mg modified release tablet according to the present invention administered daily is bioequivalent to a commercially available 150 mg twice daily 7urapf sustained release tablet.

Example 8 (comparative example) 150mg and 150mg bupropion hydrochloride formulations were prepared in accordance with US Pat.

Mob. 143.327, and pharmacokinetic parameters and relative bioavailability data were assessed for bioequivalence.

The proportions of the components used in the compositions of the core, first and second shells are shown in Table 25:

Table 25

Components

Bupropion NSI 150.00 93.75 300.00 93.75

Binder! 5.30 3.31 10.6 3.31

Lubricant? 4.70 2.94 9.40 2.94

Purified water 110.00 x 220.00 x 11111111 Pershaobolonia.:7/7/:;// Z-

Water-insoluble, water-permeable, film-forming polymer" 10.96 60.8 14.40 60.0095

A water-soluble polymer? 4.70 26.10 6.47 26.96

Plasticizer 2.34 13.01 3.13 13.04

Ethyl Alcohol3 190.00 x 230.50 x

Isopropyl Alcohol 99953 10.00 х 12.35 х 11111111 Drugaobolonyi.u///7/:/:// Av

Methacrylic acid copolymer" 7.15 63.00 11.66 63.02

Glidant? 2.30 18.70 3.45 18.65

Plasticizer 2.25 18.30 3.39 18 32

Purified water 48.00 x 72.20 x 1 Polyvinyl alcohol 2 Glyceryl behenate (Tolerate! 888 ATO)

Evaporation in the drying process 4 Ethyl cellulose 100 Rgetisht (Etose!F) with Polyvinylpyrrolidone (KoiPdopF 90e) 6 Polyethylene Glycol 1450 (SagrozhakhFf) 7 poly(methacrylic acid, methyl methacrylate) 1:1 (Eidgadikyu I 30 0-55) 8 Plasticizer is a combination of polyethylene glycol 1450 and triethyl citrate in a ratio of 2:1 with silicon dioxide (Zuioidef 244)

Tablets were produced according to the patent "327.

A pilot, three-way, multiple-dose, open-label, fasted, comparative bioavailability study of bupropion hydrochloride tablets (2 x 150 daily) manufactured in accordance with the 327 patent (the 327 patent formulation) was conducted in comparison with commercially available 7urapf tablets sustained-release (1x150 mg twice daily) and Uu/eiIriihipF tablets (three times daily) in normal, healthy, non-smoking, female and male subjects. The aim of this study was to evaluate the relative bioavailability of 150 mg of bupropion hydrochloride according to the composition of the patent "327 (2 x 150 daily) in comparison with 150 mg tablets of 7urapF with delayed release (15 mg twice a day) and 100 mg tablets of UUePriyipF (1 x 100 mg three times a day) under the conditions of a single dose or stationary conditions on an empty stomach.

Table 26 shows the profiles of the mean (and standard deviation) time of concentration in the plasma of bupropion (ng/ml) under the conditions of a single dose:

Table 26 (hours) according to patent "327 (A) | (1x15Omg twice a day) (B) | (3x10Omg three times a Day) (C) 0.0 11.7153.55 8.2512.14 30.01-17.82 1.0 11.08:2-2.90 53.87414 .58 113.91-440.96 2.0 12.95:4.38 75.965413.83 104.04-20.62 4.0 60.60ж224.59 83.71-412.49 58.455212.90 5.0 нд нд 45.92210.65 6.0 98.23231.28 64.03213.95 85.5480.91 7.0 нд нд 104.45239.11 8.0 82.63223 .84 41.6957.81 ND 9.0 ND 76.795415.73 16.0 Sun 86.15537.20 58.53515.44 18.0 32.4659.52 55.48413.29 Sun 20.0 Sun Sun 33.45527.40 24.0 20.2155.28 21.8157.77 24.141-6.03

Table 27 presents the mean (and standard deviation) pharmacokinetic data for bupropion after taking the tablets shown in Table 25:

Table of 27 values standard deviation n-15 n-15 n-15

ACiso-ha (ngoh/ml) 1154.655244.28 1301.052214.94 1622.892318.02

Stakh (ng/ml) 103.77228.13 112.68:37.06 163.10-56.84

Ttah (HOURS) 6.4011.88 11.0755.85 6.8755.60

The results of the analysis of relative bioavailability for AOso-»a (ng.h/ml) and Stakh (ng/ml), which are shown in Table 27, transformed using a natural algorithm and summarized in Table 28:

Table 28 where Fashion is waiting | not EC TK 9096 S.I. average ny pin 9095 S.I. averages I PN geometric coefficient of variation geometric coefficient of variation composition according to patent 327 2ubape composition according to compared with

Umeibigypv

Table 29 shows the mean (and standard deviation) steady-state plasma concentration-time profiles for bupropion (ng/mL) for the tablet formulation shown in Table 25:

Table 29 (hours) in accordance with the patent "327 1x15MG twice a day) ZH10MG three times a day) 0.0 0.00520.00 0.00 0.0 22.2215.80 34.1258.51 27.11578.31 0.0 21.5856.21 32.7059.94 27.33578.79 0.0 23.448.31 31.9628.83 28.715211.05 1.0 21.4717.06 64.22118.93 112.09529.65 2.0 24.3758.77 90.76218.63 116.66.27.01

4.0 87.61536.30 94.975219.30 61.94516.35 5.0 нд НД 49.43213.56 6.0 101.395225.48 73.35:217.94 85.34552.23 7.0 НД нд 112.05246.38 8.0 77.06516.40 52.56211.74 нд 9.0 нд НД 87.11523.77 11.0 НД нд 55.49517 .50 12.08.88516.23 31.2329.05 115.93253.59 13.0 ND 39.8612.55 24.0 23.3026.75 33.1529.39 29.49210.09 48.01420 12.02 12.02: 54.84 11.1124.68 1.35:51.53

Table 30 presents the mean (7 standard deviation) pharmacokinetic data for bupropion under steady-state conditions after administration of the tablets shown in Table 25:

Table 30 averages standard deviation p-15 p-15 p-15

ATCiso-ha (ngoh/ml) 1251.455257.24 1554.775293.70 | 1728.315374.54

Stakh (ng/ml) 112.24526.42 119.77527.76 156.19532.27

Ttah (HOURS) 5.3351.23 11.4755.04 9.0024.14

The results of the relative bioavailability analysis for AOsSo-ha (ng'h/ml) and Stakh (ng/ml), which are shown in Table 30, transformed using a natural algorithm and summarized in Table 31:

Table 31

Correlation Intrasubject Correlation Intrasubject 9096 S.I. average ny pin 9095 S.I. mean i m geometric coefficient of variation geometric coefficient of variation

Composition according to the comparison with 7ubape

Composition of patent "327 y | 6495-8290 73 20.069о 624905-829о 72 22.6590 compared With

Measure

Pharmacokinetic data and relative bioavailability data show that the 9095 SI for the formulation of the '327 patent does not meet the FDA's proposed threshold of 80-12595 for the product to be considered bioequivalent. Thus, these data show that the formulation, respectively to the "327 patent, is not bioequivalent to tablets available on the market 2ubapelueypyrshpe 5A or

Me ryiipFd),

The solution of bupropion in NOI for 150 mg tablets with a modified release of OA - 160.7 SHU we dyank, as pe that I x 5, K.L: t v " zh 3 ranu is i ; w ) i" ovo i. p

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Figure 1A

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Moment of time (monthly)

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Moment of time (months)

Fig28 200 ! o Bupropiom in NSI for tablets with modified release

I "- and in accordance with this invention, 2 x 150 me daily -0- of Bupropion in HER for modified-release tablets and according to this invention, 300 mg daily 7 g : and I

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In accordance with the present invention, 150 me daily after meals in / -

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Short circuit | according to the present invention, 150 mg daily after weight gain

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And what /k, according to this invention, 150 mg of daily food g: a a. -k- Tablets Bubavp, 150 mg every day on an empty stomach 1, -a- Tablets Chewable, 150 mg daily after meals on the following day: g ss ІІ 8 Б ,

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Time (an hour

FIGAE

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According to this invention, 300 IU daily after meals

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Claims (53)

1. A modified-release tablet comprising: (1) a core comprising an effective dose of a pharmaceutically acceptable salt of bupropion and conventional excipients; (ii) a first release-controlling shell surrounding said core, said release-controlling shell consisting of a water-insoluble, water-permeable, film-forming polymer and a water-soluble polymer, wherein the ratio of water-insoluble, water-permeable, film-forming polymer to water-soluble polymer is from 3:4 to 5:3; and (i) a moisture-resistant layer surrounding said first release-controlling shell, said moisture-resistant layer consisting of an enteric polymer 1 penetration enhancer, and may contain a plasticizer, and wherein the penetration enhancer is 20 90 to 40 95 of the moisture-resistant layer in dry condition; moreover, the specified tablet with modified release is bioequivalent to UMePrytiapFf or 7ubaPF/UePrinipF 5K tablets. per day when taking one dose of the specified modified-release tablet by a patient who needs such an intake. 2. A tablet with a modified release according to item I, and more than 10 90 of a pharmaceutically acceptable salt of bupropion is released within 2 hours in a 0.1M solution of NSI at 75 rpm. or not less than 75% of the pharmaceutically acceptable salt of bupropion is released within 45 minutes in a buffer of pH 6.8. 3. A tablet with a modified release according to item I or 2, and said tablet with a modified release presents such a dissolution profile that after about 2 hours no more than 20 90 of the content of a pharmaceutically acceptable salt of bupropion is released, after about 4 hours it releases from about 15 o to about 45% of the pharmaceutically acceptable salt of bupropion, after about 8 hours, from about 40,905 to about 90,905 of the pharmaceutically acceptable salt of bupropion is released, and after about 16 hours, not less than about 80,90% of the pharmaceutically acceptable salt of bupropion is released. 4. The modified-release tablet according to any of items 1-3, in which the indicated pharmaceutically acceptable salt of bupropion is bupropion hydrochloride. 5. The modified-release tablet of any one of claims 1-4, wherein the bupropion content is at least about 94% by weight of the dry weight of the core. b. A modified-release tablet according to any one of claims 1-5, wherein the core also contains a binder. 7. A modified-release tablet according to item b, in which said binder is from about 1 to about 6 percent by weight of the core in the dry state. 8. A modified-release tablet according to item b or 7, in which the binder is selected from the group consisting of modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcohol, and any combination thereof. 9. The modified-release tablet according to any one of claims 1-8, wherein the core also contains a lubricant. 10. The modified release tablet of claim 9, wherein said lubricant comprises from about 1 to about 6 weight percent of the dry core. 11. The modified-release tablet of claim 9 or 10, wherein said lubricant is selected from the group consisting of glycerol behenate, stearic acid, hydrated vegetable oils, and any combination thereof. 12. The modified-release tablet of any one of 1-11, wherein said water-insoluble, water-permeable, film-forming polymer comprises from about to about 60 percent by weight of said release-controlling coating in the dry state. 13. The modified-release tablet according to any of items 1-12, wherein said water-insoluble, water-permeable, film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl alcohol, and any combination thereof. 14. The modified-release tablet of any one of claims 1-13, wherein said plasticizer comprises from about b to about 30 weight percent of said release-controlling coating in the dry state. 15. The modified release tablet according to any of items 1-14, wherein said plasticizer is selected from the group consisting of polyols, organic esters, oils/glycerides, and any combination thereof. 16. The modified-release tablet of any one of claims 1-15, wherein said water-soluble polymer comprises from about 25 to about 50 weight percent of said release-controlling coating in the dry state. 17. The modified-release tablet according to any of items 1-16, wherein said water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, and any combination thereof. 18. The modified-release tablet according to any of items 1-17, wherein the ratio of water-insoluble, water-permeable, film-forming polymer: plasticizer: water-soluble polymer is from 3:1:4 to 5:1:3. 19. The modified-release tablet according to any one of 1-17, wherein the ratio of water-insoluble, water-permeable, film-forming polymer: plasticizer: water-soluble polymer is from 7:2:6 to 19:5:18. 20. The modified-release tablet of any one of claims 1-19, wherein the weight gain after application of the release-controlling coating is from about 390 to about 3090 of the dry weight of the core. 21. A tablet with a modified release according to any item from 1-20, where the amount of the specified enteric polymer is from 30 905 to 90 90 by weight of the moisture-resistant layer in the dry state. 22. The modified-release tablet according to any of items 1-21, which consists of about 150 mg of the specified pharmaceutically acceptable salt of bupropion, and the amount of the specified enteric polymer varies from 1 905 to 390 of the weight of the tablet in the dry state and is from 55 95 up to 70,905 mass of the moisture-resistant layer in the dry state. 23. The modified-release tablet according to any of items 1-21, which consists of about 300 mg of said pharmaceutically acceptable salt of bupropion, and the amount of said enteric polymer ranges from 1.5 90 to 3.0 90 of the dry weight of the tablet and is from 30 9Uo to 90 905 mass of the moisture-resistant layer in a dry state. 24. The modified-release tablet according to any of items 1-23, wherein the enteric polymer is an acrylic polymer. 25. The modified-release tablet of any of items 1-24, wherein said plasticizer is from about | up to about 30 percent by weight of the mass of the moisture-resistant layer in the dry state. 26. The modified-release tablet of any one of claims 1-25, wherein said penetration enhancer is about 25 percent by weight of the weight of the moisture-resistant layer in the dry state. 27. The modified-release tablet according to any of items 1-26, wherein said penetration enhancer is selected from the group consisting of silicon dioxide, colloidal silicone, lactose, hydrophilic polymers, sodium chloride, aluminum oxide, colloidal aluminum oxide, silicon oxide , microcrystalline cellulose and any combination thereof. 28. The modified release tablet according to any one of 1-27, which consists of said enteric polymer, plasticizer and penetration enhancer in a ratio of 13:2:5. 29. The modified release tablet of any one of claims 1-28, wherein the application of the moisture resistant layer to the tablet results in a total weight gain of no more than about 6 90 relative to the dry weight of the tablet. 30. The modified-release tablet according to any one of claims 1-29, wherein said modified-release tablet under fasting conditions provides a bupropion plasma Tmax of about 3 hours to about 8 hours (Th) after administration of the modified-release tablet. 31. The modified-release tablet of any one of claims 1-30, wherein said modified-release tablet provides a bupropion Tmax of about 60 ng/ml to about 280 ng/ml in plasma within about 5 hours (Tmax) after administration under an empty stomach. once a day 300 mg dose of the indicated bupropion hydrochloride tablet with modified release or once a day 2 x 150 mg dose of the indicated bupropion hydrochloride tablet with modified release. 32. The modified-release tablet of any one of claims 1-31, wherein said fasted modified-release tablet has an AUC for bupropion of about 840 ngh/ml to about 2850 ngh/ml after fasting once a day 300 mg dose of the indicated bupropion hydrochloride tablet with modified release or once a day 2 x 150 mg dose of the indicated bupropion hydrochloride tablet with modified release. 33. The modified-release tablet of any one of claims 1-32, wherein said modified-release tablet has an AUC) for bupropion of about 840 ng. h./ml to about 3000 ng. h./ml after taking on an empty stomach once a day 300 mg dose of the indicated bupropion hydrochloride tablet with modified release or once a day 2 x 150 mg dose of the indicated bupropion hydrochloride tablet with modified release. 34. The modified-release tablet of any one of items 1-33, which, upon administration of a single dose of bupropion by a patient in need thereof, provides a Bupropion Tmax of from about 60 ng/ml to about 280 ng/ml for from about 3 hours to about 8 hours (Tmax) and AOC(o-o) for bupropion ranges from about 800 ng. h./ml to 2850 ng. h./ml. 35. A modified-release tablet according to any of items 1-34, wherein said modified-release tablet is administered at a dose of 300 mg once a day or 2 x 150 mg doses once a day by a patient in need of such administration, on an empty stomach bioequivalent to tablets UePrshtipF or LubapF/UePrinipf 5K per day. 36. The modified-release tablet according to any of items 1-35, wherein said modified-release tablet is bioequivalent when administered at 2 x 150 mg doses once daily or at 300 mg doses once daily by a patient in need of such administration tablets UePrinipf) or Lubape/MePrinipF 5K. per day and does not affect the effect of food. 37. A modified-release tablet according to any item from 1-36, and the specified modified-release tablet is bioequivalent to UePrinipF or 7ubaPF/UMePrinipF 5K tablets per day, at a single dose of the specified modified-release tablet when taken by a patient who requires such administration , on an empty stomach and after a meal. 38. The modified-release tablet according to any item from 1-37, and the specified modified-release tablet when taken at a dose of 300 mg once a day by a patient who requires such an intake, on an empty stomach, is bioequivalent to UMePrinip F tablets taken 1 x 300 mg three times a day in a stationary mode. 39. The modified-release tablet according to any one of items 1-38, wherein said modified-release tablet when administered at a dose of 300 mg once daily by a patient in need of such administration, on an empty stomach, is bioequivalent to 7urapf tablets taken 1 x 150 mg twice a day in a stationary mode. 40. The modified-release tablet according to items 1-39, and the moisture content is no more than about 0.4905 in the specified modified-release tablet after about 10 days of storage in an open cup at a temperature of 40 °C and 2 2 °C and a relative humidity of 75 9 /0 5 90. 41. The modified-release tablet according to items 1-40, and the moisture content of the specified modified-release tablet is no more than about 1,905 in the specified tablet after about b months of storage at a temperature of 40 "C - 2 C and a relative humidity of 75 0 5 90 . 42. The modified-release tablet according to items 1-41, wherein said tablet contains at least about 95 µg of bupropion hydrochloride of nominal quality after storage for 12 months at a temperature of 25 °C 2 °C and a relative humidity of 60 90 5 °C. 43. A modified-release tablet according to items 1-42, wherein said tablet contains at least about 9590 bupropion hydrochloride of nominal quality after storage for 18 months at a temperature of 25 C 2 "C and a relative humidity of 60 90 5 to. 44. The modified-release tablet according to items 1-43, and said tablet contains 150 mg of bupropion hydrochloride. 45. The modified-release tablet according to items 1-43, and said tablet contains 300 mg of bupropion hydrochloride. 46. A modified-release tablet according to claims 1-45, which does not affect the effect of food. 47. The composition of the modified-release tablet according to item |: (1) a core containing an effective dose of bupropion hydrochloride, polyvinyl alcohol, glyceryl behenate, said bupropion hydrochloride being at least about 94% by weight of the dry weight of the core, said polyvinyl alcohol being about 3 weight percent of the weight of the core in the dry state and the specified glyceryl behenate is about 3 weight percent of the weight of the core in the dry state; (ii) a release-controlling shell covering said core completely tightly, said release-controlling shell consisting of RK 100 grade ethyl cellulose, polyethylene glycol 1450, and polyvinylpyrrolidone, said PE 100 grade ethyl cellulose being from about 45 to about 50 percent by weight by weight of the dry release control coating, said polyethylene glycol 1450 is about 12 weight percent by weight of the dry release control coating, and said polyvinylpyrrolidone is about 25 to about 50 weight percent by weight of the release control coating in in the dry state, and the amount of said release control coating applied is from about 9 to about 15 percent by weight of the weight of the tablet core in the dry state; and (iii) a moisture resistant layer surrounding said release control shell, said moisture resistant layer consisting of a copolymer of methacrylic acid, polyethylene glycol 1450, triethyl citrate, and silicon dioxide, said methacrylic acid copolymer being about 66 percent by weight of the dry weight of the moisture resistant layer , the specified polyethylene glycol 1450 and triethyl citrate make up about 10 percent by weight of the mass of the moisture-resistant layer in the dry state in the proportion: 1 part of triethyl citrate to 2 parts of polyethylene glycol 1450, and the specified silicon dioxide makes up about 25 percent by weight of the mass of the moisture-resistant layer in the dry state, and the amount of applied specified moisture-resistant layer is no more than about 2.5 90 of the weight of the tablet in the dry state. 48. The modified-release tablet composition of claim |: (1) a core containing an effective dose of bupropion hydrochloride and conventional excipients; (ii) a release-controlling shell surrounding said core, said release-controlling shell consisting of a water-insoluble, water-permeable, film-forming polymer, a plasticizer, and a water-soluble polymer; and (iii) a moisture resistant layer surrounding said release control shell, said moisture resistant layer consisting of a copolymer of methacrylic acid, polyethylene glycol 1450, triethyl citrate, and silicon dioxide, said methacrylic acid copolymer being about 66 percent by weight of the dry weight of the moisture resistant layer , the specified polyethylene glycol 1450 and triethyl citrate make up about 10 percent by weight of the mass of the moisture-resistant layer in the dry state in the ratio: 1 part of triethyl citrate to 2 parts of polyethylene glycol 1450, and the specified silicon dioxide makes up about 25 percent by weight of the mass of the moisture-resistant layer in the dry state. 49. The composition of the modified-release tablet according to item 1: (1) a core containing about 150 mg of bupropion hydrochloride, about 5.3 mg of polyvinyl alcohol, about 4.7 mg of glyceryl behenate; (iii) a release-controlling shell surrounding said core, said release-controlling shell consisting of about 12 mg of PE grade ethyl cellulose. 100, about 3 mg of polyethylene glycol 1450 and about 9 mg of polyvinylpyrrolidone, with about 24 mg of a release control coating applied to said core; and (iii) a moisture resistant layer surrounding said release control shell, said moisture resistant layer consisting of about 4.6 mg of methacrylic acid copolymer, about 0.46 mg of polyethylene glycol 1450, about 0.23 mg of triethyl citrate, and about 1.72 mg of silicon dioxide, with about 7 mg of a moisture-resistant layer applied to the cores, which are coated with a release-controlling coating, and the specified modified-release tablet is bioequivalent to UMePrytiaF or 7ubaPF/UMePrinipyu 5K tablets, when taking a single dose of the specified modified-release tablet by a patient who needs such an administration, and the composition of the specified modified-release tablet presents such a dissolution profile that after about 2 hours about 5% of the bupropion hydrochloride content is released, after about 4 hours about 329% of the bupropion hydrochloride content is released, after about 8 hours about 74 90 bupropion hydrochloride content and after about 16 hours, no less than about 99.95% of the bupropion content is released, with a 0.1M solution of NSI at 75 rpm. and a temperature of 37 C. 50. The composition of the modified-release tablet according to item 1: (1) a core containing about 300 mg of bupropion hydrochloride, about 10.6 mg of polyvinyl alcohol, about 9.4 mg of glyceryl behenate; (ii) a release-controlling shell surrounding said core, said release-controlling shell consisting of about 13.1 mg of grade RK 100 ethylcellulose, about 3.6 mg of polyethylene glycol 1450, and about 12.4 mg of polyvinylpyrrolidone, and about 29 mg a release-controlling shell is applied to said core; and (iii) a moisture resistant layer surrounding said release control shell, said moisture resistant layer consisting of about 6.9 mg of methacrylic acid copolymer, about 0.7 mg of polyethylene glycol 1450, about 0.35 mg of triethyl citrate, and about 2.6 mg of silicon dioxide, with about 10.5 mg of the moisture-resistant layer applied to the cores, which are coated with a release-controlling coating, and the indicated modified-release tablet is bioequivalent to the UMePrytiapFf or 7ubaPF/UePrinipF 5K tablets. per day when taking one dose of the specified modified-release tablet by a patient who requires such administration, and the composition of the specified modified-release tablet presents such a dissolution profile that after about 2 hours, about 5 o of the content of bupropion hydrochloride is released, after about 4 hours, about 32 9% of the bupropion hydrochloride content, after about 8 hours, about 74% of the bupropion hydrochloride content is released, and after about 16 hours, no less than about 99,905% of the bupropion hydrochloride content is released in 900 ml of 0.1M NCI solution at 75 rpm. and a temperature of 37 2C. 51. A method of treating depression in a patient in need of such treatment, which includes prescribing to the patient modified-release tablets according to any item from 1- 52. The method according to claim 51, in which said tablet with modified release contains a dose of 300 mg. 53. The method according to claim 51, in which the indicated tablet with modified release contains a dose of 150 mg.