Mirtazapine-containing orally decomposing composition

FIELD: medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to the orally decomposition composition comprising mirtazapine. A single dosed medicinal formulation decomposing rapidly after its oral administration is bioequivalent to usual tablet but shows advantages with respect to adverse effects, effectiveness, anxiolytic effects, dream-improving effects, and acceleration of onset effect of an antidepressant agent. Invention can be used in treatment of depression.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 1 tbl, 2 ex


The invention relates to a unit dosage form for oral administration containing pharmaceutical composition of mirtazapine as an active ingredient and pharmaceutically acceptable excipients.

Mirtazapine (Remeron, Remeron®) is known as a drug for the treatment of, among other things, depression. As the antidepressant mirtazapine is a separate class of antidepressants, recognized as a noradrenergic and specific antidepressant (NaSSA), which enhances both noradrenergic and serotonergic neurotransmission through antagonism of presynaptic α2-adrenergic receptors while blocking postsynaptic serotonin receptors 5-HT2and 5-HT3.

The known pharmaceutical forms for oral administration of mirtazapine in the form of conventional tablets. Contents for therapeutic purposes, the active ingredient ranges from 15 to 45 mg of mirtazapine. The above known tablets in General are acceptable, because we are talking about their activity for therapeutic purposes and, as it proved, mirtazapine is a safe, well-tolerated and effective antidepressant. However, mirtazapine is scope for improvement. This improvement consists, inter alia, the reduction in the face-to-face action. For mirtazapine, these side effects, in particular, include increased appetite, weight gain, sleepiness during the day, sexual dysfunction, disorders of gastro-intestinal tract, edema, tremor of the legs, dry mouth, excessive sedation. In particular, for mirtazapine, it is necessary to improve some useful actions, such as improved sleep and increased anxiolytic action, and achieve an earlier onset of antidepressant action. The latter is especially important for psychiatry. Known antidepressants usually take a long period of admission, up to several weeks before the onset of their antidepressant activity. It is desirable to shorten this period, preferably to less than one week.

Improved dosage forms of mirtazapine described in the publications related to this area. In the European patent 436252 disclosed microparticles or granules used to obtain the liquid pharmaceutical composition of mirtazapine for oral administration. These granules with the introduction of the appropriate amount of water and mixing to form potable suspension of mirtazapine. In the European patent 431663 revealed stable solution of mirtazapine, suitable for parenteral or oral administration. In one the belt examined patent application PCT/EP 99/02277, describes other aqueous solution or suspension of mirtazapine for oral administration. This product differs in that it has a concentration of mirtazapine in the range from 5 to 110 mg/ml, pH range from 2.0 to 3.5, and includes a thickener. Disclosed is also a pre-prepared mixture, premix, from which you can get this oral solution or suspension, adding water, or by simple contact with the saliva of the individual subject treated. It is noted that the premix must form a solution or suspension, as described in PCT/EP 99/02277, i.e., the premix should be of such nature, to turn into a solution or suspension having the above-mentioned requirements for pH. From the point of view of the buffer capacity of the saliva of a person this means that if the premix is intended to obtain a suspension, already having a pH of 2.0-3.5, then it must contain a relatively large amount of acid.

Even if it is recognized that such alternative formulations of mirtazapine may be used, the present invention is directly connected with the development of discrete dosage units for oral administration, which can fully substitute for a well-known tablets on the market under the trademark Remenon®. In line with this objective of the present invention is to improve the action of mirtazapine prividenii in the form of a discrete dosage units for oral administration, which have the same content (the active substance), as conventional tablets, and which are bio-equivalent to conventional tablets.

The invention relates to a unit dosage form for oral administration of mirtazapine defined in the introductory paragraph, with the single dosage form is a type of composition, disintegrating in the mouth (orally disintegrating), and which includes a tool that essentially prevents the release of mirtazapine orally (i.e. in the oral cavity, but not in the gastrointestinal tract).

Thus, the discrete oral unit dosage forms have the same content (the active substance), known as the pill and that it is not obvious from a consideration of the prior art are bioequivalent popular tablets with a content of 15, 30 and 45 mg of mirtazapine. Suddenly, and without presuming to reduce all side effects for all patients, it was found that a single dosage form according to the invention can be used to make improvements in the action of mirtazapine, such as the onset of action of antidepressant within one week and reduce symptoms of side effects such as weight gain and excessive sedative effect.

The invention p is hidden in more detail below, referring to the different characteristics of the dosage units.

Unit dosage forms are discrete units suitable as a single dose for the patient is that each contains a predetermined amount of the active substance, in this case 15-45 mg of mirtazapine, for example, tablets, pills, capsules, etc.

Oral administration means that the unit dosage form is administered through the mouth of the patient, in whatever way after it was released or absorbed drug.

The pharmaceutical composition is a composition containing the active substance, either as such (and in this case, the composition is active substance), or in combination with other components, which are not recognized as active agents used in the medical purposes, and which simply contributes to the retention of the active substance. Such (inert) ingredients typically include diluents, fillers, stabilizers and other adjuvants.

Mirtazapine, which represents the connection 1,2,3,4,10,14 β-hexahydro-2-methylpyrazol[2,1-a]pyrido[2,3-C]benzazepine, as expected, includes the connection per se, as well as its pharmaceutically acceptable salts. The connection can be obtained as described in U.S. patent No. 4062848 van der Burg.

It should be borne in mind, staircases contains the center of chirality. The present invention includes each of the individual (R) and (S)enantiomers of mirtazapine and their salts in the form of, mostly free of the other enantiomer (i.e. having enantiomeric purity higher than 95% and preferably higher than 99%), as well as mixtures of enantiomers in any ratio, including a racemic mixture.

The term "pharmaceutically acceptable excipients are well-known, and its use in this field for attributing to all those, usually inert substances, which can contain a pharmaceutical composition in addition to the active substance and which, as acknowledged, are safe for this purpose. Such fillers include carriers, diluents, binders, lubricants, glidant, disintegrators, colors, corrigentov, stabilizers, etc. These types of components are known to the person skilled in the art, and they do not require further explanation. In various following guidelines, see, for example, The standard English language text Gennaro et al. Remington''s Pharmaceutical Sciences (18th ed. Mack Publishing Company, 1990, especially Part 8: Pharmaceutical Preparation and Their Manufacture)described methods of making tablets, capsules and pills and their corresponding components. Oral solid dosage forms, which mainly relates the present invention, described in Chapter 89.

The term "orally disintegrating unit dosage of lekarstvennaya the Orme" specifies the type of unit dosage forms, which relates to this invention, unlike conventional tablets. Thus, the term refers to a unit dosage forms, which, after oral administration, disintegrate in the mouth and/or esophagus, but not in the stomach or gastrointestinal tract. It usually is linked with the time raspadaemosti less than 60 seconds. Examples include effervescent tablets, bystrorastvorimaya, bystrorazvivajushchiesja (consumable) tablets, sublingual (sublingual) tablets.

For a more clear definition of the composition in accordance with the invention, reference is made to the following three fundamentally different categories of solid dosage forms, which may vary, but they all serve for the introduction of drugs through the mouth:

(a) a unit dosage forms, which must be swallowed and should disintegrate in the stomach or gastrointestinal tract, so that the drug would be released in the gastrointestinal tract; absorption (suction) of the medicinal product occurs through the gastrointestinal tract; classic examples include compressed tablets and capsules filled with granules;

(b) disintegrating in the oral cavity sublingual or transbukkalno (hominids) a unit dosage form; analisa effectively to swallow or chew, as they rapidly disintegrate in the mouth after contact with saliva; they release the drug locally in the sublingual or buccal pocket; absorption (suction) of the medicinal product occurs through the sublingual or buccal mucous membrane; examples include sublingual or cheek tablet;

(c) disintegrating in the oral cavity unit dosage forms that cannot be swallowed whole, but which disintegrate in the mouth spontaneously or by grinding or sucking; the drug is released from disintegrated particles in the esophagus or stomach, after which there is absorption (suction) through the gastro-intestinal tract; examples: effervescent tablets or pills of many particles, each with covered or in some other way encapsulated drug or medicine that is not inherently absorbed absorbed through the mucous membranes (oral cavity).

According to the invention orally disintegrating tablets are tablet category (C), i.e. such nature that mirtazapine is absorbed at least for the most part, in the same way as through the normal oral route. In the case of sublingual or hominids ways that are designed to have a direct absorption (in usuwanie) of the active substance through the mucous membrane, not through the first transformation with the passage of hepato-gastro-intestinal system, this tablet is usually not equivalent bioavailability of conventional oral tablets. In accordance with the invention is designed dosage form of mirtazapine, which from the viewpoint of principle comparable with existing conventional compressed tablets, but with an unexpected preimuschestvami detected in the decay in the mouth.

Pharmaceutical compositions, disintegrating in the oral cavity, known to specialists in this field. There are references, for example, in EP 636364, EP 737473, U.S. patent 5178878, U.S. patent 6024981 and U.S. patent 5464632. All of them are related to the composition of the particles of the active ingredient, where the particles are linked together so quickly disintegrate after oral administration. In the patent EP 636364 raspadaemost is carried out by means capable of dissolution in water, shrinking, carbohydrate and a binder. In U.S. patent 5178878 disclosed pharmaceutical dosage form contains microparticles that include in the tablet loosening tool. When the pill is taken orally, sparkling (blowing), loosening tool (disintegrator) promotes rapid raspadaemosti tablets and contributes to the release of microparticles and ingestion of particles before Pharma is efticiency component will release from the microparticles. In U.S. patent 5464632 revealed another, capable of rapidly disintegrating tablet, consisting of many particles. It contains a mixture of fillers, which is suitable to give a pill that speed raspadaemosti at which it disintegrates in the mouth in less than 60 seconds, where the active substance is present in the form of coated microcrystals or microgranules. In U.S. patent 5225197 revealed another pharmaceutical composition that may be suitable as an orally disintegrating composition of the present invention. It is a chewable tablet comprising a drug dispersed in chewing basis, such as mannitol, together with sparkling pair, such as citric acid - sodium bicarbonate.

The funds, which essentially prevents oral release of mirtazapine, have a feature that prevents the absorption of mirtazapine as in the case when it comes to sublingual or cheek part. Although theoretically, for example, can be designed salt of mirtazapine, which could prevent oral absorption, it is preferable that connection, as such, remained unchanged, and the tool that prevents oral release, in fact, would protect mirtazapine until then, until he swallows. Such CPE is of known not only from publications, related to oral disintegrating dosage units, but also from publications related to the prolonged release compositions, such as EP 318328. Suitable means is a coating layer on the active agent, which belongs to this type, which usually remains intact in the mouth and usually dissolves, disintegrates (which opens or otherwise)to release the active substance, when required. Although, in the full sense of the word, prolonged release coating are not preferable, taking into account the required bioequivalence metered units in accordance with the present invention, conventional tablets, the person skilled in the art can, without undue experimentation, to test these coatings on mirtazapine and set the desired time of the release in the stomach with a simple test for dissolution in the acidic environment. Such tests are described in the above reference, Gennaro, Chapter 31.

Suitable coatings for active substances, among others, described in the above publications relating to oral disintegrating unit dosage forms, EP 636364, U.S. patent 5178876 and U.S. patent 5464632. ER 636364 concerns several masking (unpleasant) taste of songs with the same success PR is suitable as coatings, preventing oral release of mirtazapine. Reference is made to the methods and materials disclosed in EP 636364, and not the repetition of this disclosure fully in the description. These coatings can provide a mixture, as described in the mentioned patent. It is preferable to make the coating of only one substance, which is in compliance with EP 636364 can be hydroxypropylcellulose, hydroxyethyl cellulose, Eudragit® E100 (methylaminomethyl-methacrylate and neutral esters of methacrylic acid, available from Rohm Pharma GmbH) or hypromellose. In U.S. patent 5178878 revealed similar protective materials, including other materials Eudragit®.

It should be borne in mind that a single dosage form according to the invention does not require an unnecessarily large amount of acid, which is usually necessary, if after contact with saliva should be reached a pH value of from 2 to 3.5. Essentially, for oral solution or suspension according to PCT/EP 99/02277 to prevent local anesthetic action, requires a low pH. In accordance with the present invention a tool that prevents the selection of mirtazapine orally, at the same time can function as a masking of unpleasant taste, as well as a protective layer in the case of local anastasiou is his actions.

Due to the alkaline nature of mirtazapine, a connection was found, turned out to be unexpectedly appropriate to provide a polymer coating, which has a closed structure at neutral, slightly alkaline pH of 7.4, found in the mouth, and which has a more open structure in the environment of high acidity of the stomach, thereby highlighting mirtazapine essentially the same way as a standard tablet. Such polymers, which are believed to manifest their effect, undergoing conformational change depending on pH, well-known specialist in this field. Preferred of the above-mentioned Eudragit®.

As noted above, orally disintegrating unit dosage forms often include small particles, microparticles or other substance in the form of microparticles. These particles can include an active ingredient. In this case, the particle itself can function, preventing the oral secretion of mirtazapine contained in it. Or, as is preferable in the case when it comes to mirtazapine, such small particles cover the active substance. More preferably, the small particles was represented by the so-called "non-pareils", which are known in this area as highly uniform particles of sugar, with a clear spherical (like the Arica) form. In this area it is known the use of such non-pareils for application of medicines. As mentioned above, mirtazapine, in turn, is preferably covered with a polymer, such as Eudragit®.

Summarizing, the oral unit dosage form of the present invention is a new combination of antidepressant, mirtazapine, in unit dosage form oral disintegrating type. A unit dosage form, rapidly decaying after oral administration, bioequivalency conventional tablets, but can lead to advantages in terms of adverse action and the beginning of the action (antidepressant). It should be borne in mind that the onset of action of antidepressant is usually not associated with time raspadaemosti, because the onset of action is usually considered on the basis of weeks, while the tablet given daily. An antidepressant can be defined in several ways, mainly by using a rating scale of depression on the Hamilton scale clinical global observations and/or scale depression scores on the Montgomery Asberg.

In addition, the invention relates to the use of mirtazapine for obtaining a medicinal product for the treatment of depression, where the drug represents a single dosage Fort is in the above-mentioned oral disintegrating type, and where, basically, prevented the release of mirtazapine orally (in the mouth). In addition, the invention relates to a method of treatment comprising administration to the patient-the person in need of such treatment at least one unit dosage form of the aforementioned oral disintegrating type, and where mirtazapine mostly protected from being released orally. In all cases, it is preferable that mirtazapine is not allocated in oral more than 90% and most preferably not allocated at all. The unit dosage form preferably comprises mirtazapine coated as described above.

The invention is further expanded by referring to the following examples.


Receive oral disintegrating tablet containing 30 mg of mirtazapine each, using the following excipients: mannitol, crosspovidone, sodium bicarbonate, citric acid, microcrystalline cellulose, aspartame, magnesium stearate, corrigent, inert particles uniform in particle size of the spherical shape of sugar (non-pareils), povidone, hypromellose, Eudragit E100. The above particles (non-pareils) put a layer of coating of mirtazapine in the usual way. These are then covered with mirtazapine particles covered with a layer of Eudragit E100 way, the description of the figures in EP 636364. Then, the resulting coated particles combine with the remaining excipients in the effervescent composition in accordance with example 1 of U.S. patent 5178878.


Test bioequivalence oral disintegrating tablets of mirtazapine in accordance with example 1, in comparison with the tablet available on the market that contain the same number of mirtazapine (30 mg), which is known under the trade name Remeron®after a single oral administration in conditions of starvation.

Method: an open, randomized, two treatment, two period, two sequence crossover study.

The number of subjects in the trial was attended by forty subjects (20 men and 20 women)who all completed the test. Forty subjects received two treatments.

Treatment T (test): single oral dose of one tablet in accordance with example 1 under conditions of starvation. With tablet water is not allowed.

Treatment R (comparison): single oral dose of one pill Remeron® (containing 30 mg of mirtazapine) in conditions of starvation, followed by 200 ml does not contain carbonate water.

Duration of treatment: two single dose separated by a leaching period of at least two weeks.

Pharmacokinetics: taking blood samples to determine the concentration of mirtazapine before the dose of 15, 30, 45, 60 and 90 minutes and 2, 2,5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours after administration of mirtazapine. From the individual curve "concentration in the plasma depending on time receive the following parameters:max, tmax, PPKt(AUC0-tlast), t1/2that λzACC0-((AUC0-∞). From the primary parametersmax, PPK0-tACC0- ∞ count parametric evaluation point of the true relationship "test/comparison with their 90% confidence intervals (multiplicative model)obtained from analysis of variance. The parameters considered bioequivalent if the confidence interval of 90% is entirely within the realm of acceptance of hypotheses (0,80-1,25). For tmaxtested classical hypotheses using the ANOVA analysis.

Results: see table 1.

Conclusion: comparative structure and the test structure are bioequivalent to the maximum concentration, area under the curve from zero up to the time of the last measurable concentration and area under the curve from time zero up to infinity.


Testing of onset of antidepressant action, as well as body mass, sexual function and other impacts associated with mirtazapine, as a result of the introduction of subjects-people with a Major Depressive Episode (coz the ACLs DSM-IV criteria) a unit dosage form in accordance with the invention. Subjects were evaluated with the purpose of establishing the validity of an antidepressant within the first and second week of treatment. Subsequent evaluations were done every two weeks.

Table 1
The results of tests of bioequivalence
Score points90% DEConclusion

1. A unit dosage form for oral administration comprising the pharmaceutical composition of mirtazapine or its pharmaceutically acceptable salt, pharmaceutically acceptable excipients and a layer that covers mirtazapine and protects mirtazapine from oral release, and the unit dosage form is an oral disintegrating and the covering layer dissolves in the acidic environment of the stomach.

2. The unit dosage form according to claim 1, in which the layer is a polymer.

3. A single dosage of Lekarstvo the I form according to claim 2, in which the polymer is derived from monomers of methylaminoacetaldehyde and neutral methacrylic ester.

4. The unit dosage form according to claim 3, in which mirtazapine, in turn, deposited on inert particles.

5. The unit dosage form according to claim 4, in which the particles are of uniform particles of spherical shape (non-pareils).


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