Oral bystrorastvorimaya composition dopamine agonists

 

(57) Abstract:

The invention relates to the field of pharmacology, and relates to pharmaceutical compositions for oral administration. The invention consists in that the composition comprises a carrier and a dopamine agonist as an active component, characterized in that the composition is presented in the form bistrotdepierrerue dosage form intended for quick release of the active ingredient in the oral cavity. There are also such compositions which additionally contain antervasna tool and/or an opioid antagonist. In addition, we offer a process for preparing such compositions, use of such compositions for the treatment and/or assessment of the degree of development of Parkinson's disease and therapeutic products and kits for the administration of a dopamine agonist and joint administration of a dopamine agonist and antivoltage funds and/or opioid antagonist. The invention provides for the reduction of unwanted peripheral effects. 10 C. and 16 h.p. f-crystals, 2 ill., 17 table.

This invention relates to pharmaceutical compositions, methods of preparing such compositions, use of such compositions for the treatment and/or assess the extent of radolin") and the joint administration of a dopamine agonist and antivoltage funds and/or opioid antagonist.

Parkinson's disease is a progressive neurodegenerative violation arising from loss of cell bodies dofaminergicheskih neurons from the black substance (substantia nigra and degeneration of nerve terminala in the striatum (the striatum corpus) on the background of low levels of dopamine in the black matter and the striatum. Parkinson's disease is characterized by chronic progressive dysfunction of the activity, and its main symptoms are tremor at rest, rigidity of muscles and a reduction in the frequency of voluntary movements (hypokinesia), accompanied by difficulties with walking at the end and the beginning of the movement, as well as when performing repetitions. Permanent tremor superimposed on the hypertonicity of muscles-antagonists and the beginning of the movement is becoming more difficult and slow. In advanced cases the movement of patients actually become "frozen" and patients lose the ability to move independently. Studies have shown that symptoms of Parkinson's disease appear when the content of dopamine in the striatum is reduced to 20-40% of normal.

Because Parkinson's disease is associated with loss of dopamine striped body, it is usually treated with drugs that samedeutz in the brain into dopamine, and that dopamine exerts a therapeutic effect. However, despite the fact that levodopa well absorbed in the small intestine, a significant part of it is inactivated by the action of monoamine oxidase in the gut wall. In addition, the half-life of levodopa in plasma is short, and about 95% of the drug is converted to dopamine in peripheral tissues, where widespread copadichromis, resulting in less than one percent of the drug enters the brain. Therefore, levodopa must be injected frequently and in large doses. In addition, the formation of dopamine in the peripheral dnah causes unwanted side effects. Thus, levodopa is usually administered in combination with other drugs that increase the action of levodopa on the brain and minimizes its peripheral effects. In particular, levodopa usually used in combination with inhibitor activity dofadekarboksilazy peripheral tissues, unable to cross the blood-brain barrier, such as carbidopa, which inhibits the collapse of levodopa to dopamine outside the brain, thus reducing the unwanted peripheral effects. The effect of the inhibitor is also something about Bolotova, that also reduces peripheral side effects. In addition, a peripheral dopamine antagonist, which does not penetrate the blood-brain barrier, such as domperidone, can also be introduced to reduce nausea and vomiting as side effects of levodopa.

In addition to the above-mentioned side effects other adverse effects associated with prolonged use of levodopa. In particular, many patients develop involuntary goreaphobia movements that are the result of excessive activation of dopamine receptors. These movements usually cover the face and limbs, and can be carried very hard. Such movements disappear, if you reduce the dose of levodopa, but this causes the return of rigidity. Moreover, the boundary between desirable and undesirable effects, apparently, is gradually becoming more narrow as increasing the time of treatment, levodopa. The traditional method of dealing with this effect represents an increase in the frequency of introduction of levodopa, while maintaining a constant total dose. This approach reduces the deterioration at the end of dose and reduces the likelihood of patients dyskinesia, a cat who is the development of rapid fluctuations in clinical state of the patient, when there are sudden transitions from mobility to immobility and, conversely, during time intervals ranging from several minutes to several hours. This phenomenon is known as "the effect on and off, the state of "on" is the preferred condition for which can be achieved almost normal motor function, and where the state "off" is characterized by dystonic postures during periods of reduced mobility. Indeed, as a result of this influence can be such a sudden loss of mobility that the patient may abruptly stop when you walk or be unable to rise from a chair, on which he normally sat down a few minutes ago. This effect is usually not my steps manipulation doses of levodopa, and may require treatment with alternative drugs.

In addition to the above-mentioned side effects with long-term use of levodopa found that the effectiveness of levodopa gradually decreases with increasing time of its use until then, until he becomes completely ineffective. There was also an increase in the number of cases of malignant melanoma in the development of malignant melanoma. Thus, the use of levodopa for the treatment of Parkinson's disease is far from ideal.

An alternative approach to the treatment of Parkinson's disease is the use of drugs that have diaminophenyl effect. Such medicines in General known as dopamine agonists, because they directly stimulate dopamine receptors in the area nigrostriatal tract deficiency in him of dopamine. Unlike levodopa the dopamine agonists do not require conversion in the brain in an active connection. The dopamine agonists are also effective in patients with advanced stages of Parkinson's disease, when levodopa becomes ineffective because they (agonists) act directly on dopamine receptors and they are not affected by the presence of lack of dopamineproducing nerve cells in these patients. However, the effect of dopamine agonists on dopamine receptors also causes unwanted dofaminergicheskie effects, such as nausea, vomiting and extrapyramidal effects that could undermine the health, and some dopamine agonists such as apomorphine, are connected, especially when used in high doses, with additional unwanted side effects, the tin and nature of side effects can affect the way drug administration. For example, in the study of action of apomorphine have been studied by various methods of administration of this drug. However, in oral introduction of tablets apomorphine need to enter large doses to achieve the desired therapeutic effect, as apomorphine, introduced in this way is subjected to intensive metabolism in the small intestine and/or liver before entering the systemic circulation (the primary effect of passing). In addition, studies of long-term action such input oral forms stopped 7-10 days because of unexplained increase in blood urea nitrogen. Sublingual injection of apomorphine tablets caused severe disease with a positive consumption with the advent of ulceration of the mucous membrane of cheeks half of the patients with this method of treatment. Intranasal introduction was caused by a temporary blockage of nasal breathing, feeling the burn and swelling of the nose and lips, and some of the surveyed patients had to be discontinued, whereas the occurrence of chemically induced inflammation of the nasal mucous membrane. Thus, the only satisfactory by injection of apomorphine, which can be avoided to a high degree of metabolism during the initial admission, as biomarine is a liquid preparation for subcutaneous injection or subcutaneous infusion. Even in this case, subcutaneous administration is not possible to avoid the side effects of normal dopamine agonists, such as nausea and vomiting, and subcutaneous administration, be it injection or infusion, it is not easy to perform, especially in patients whose motor function is already compromised, and in this connection it is necessary to educate patients and staff care. In addition, the injection site should be changed every 12 hours to minimize the risk of discoloration of the skin and formation of nodules. From the point of view of these problems it is not surprising that the use of dopamine agonists, such as apomorphine in the treatment of Parkinson's disease most often confined to the treatment in the "off" period, caused by the treatment of levodopa, despite the obvious clinical benefits of these drugs over levodopa.

From the above, it seems obvious that it would be highly desirable from a clinical point of view to find the way for the introduction of dopamine agonists, such as apomorphine, which would be simple to introduce the patient, reducing in this regard, the need to monitor the introduction, and which bypassed the metabolism in primary hit in the liver. Thus, the present invention is the pharmaceutical composition is that the composition, what is bistrotdepierrerue dosage form intended for quick release of the active ingredient in the oral cavity.

Discovered that such bystrotverdeyuschie dosage forms induce registernow absorption of the active component, that is the absorption of the active component from the part of the digestive way, which is to the stomach. The term "registraciya absorption thus includes the absorption in the mucous membranes of the cheeks, sublingual, oropharyngeal absorption and absorption in the esophagus. The dopamine agonists which are absorbed by such registrales absorption, proceed directly into the systemic circulation, thus avoiding the metabolism in the primary flow in the liver. Thus, the physiological availability of dopamine agonists which are absorbed in this way, can also be increased. This means that the dose of these dopamine agonists can be reduced while still preserving its desired therapeutic effect and that this dose reduction will be accompanied by a corresponding reduction of unwanted side effects.

In addition, clinical studies have shown that 23-52% of patients with the disease Parkinso the fast-acting dosage forms have an additional advantage in that, they will quickly dispergirujutsja mouth, minimizing thus the above-mentioned problems, as together with them will not introduce large amounts of water. Thus, it is expected that such bystrotverdeyuschie dosage forms will be easier to transfer patients and will facilitate the introduction of the medical staff.

One example bistrotdepierrerue dosage forms are described in U.S. Patent 4855326, in which the fusible fiber agent carrier, such as sugar, combined with the active ingredient and the final mixture is attached to the fiber form of the drug "candy floss". Fiber product "candy floss" then compacted in bistrotdepierrerue highly porous solid dosage form.

U.S. patent 5120549 reveals bistrotdepierrerue binder system, which is obtained by primary curing of the binder system, dissolved in the first solvent, and the subsequent contact of the hardened matrix with a second solvent, easily miscible with the first solvent at a temperature below the point of solidification of the first solvent; the elements forming the matrix and the active ingredient is poorly soluble in the second dissolve the matrix.

U.S. patent 5079018 reveals bistrotdepierrerue dosage form, which includes a porous fiber structure soluble in water Hydra together with gel or foam material, pre-hydrated with water treatment and solidified in the hydrated state in the presence of the agent, hardener, and dispersed using a liquid organic solvent at a temperature of about 0oC or lower to reclaim space occupied by the hydrating liquid.

Published international application WO 93/12769 (PCT/JP93/01631) describes bystrotverdeyuschie dosage form very low density formed by forming a jelly agar, liquid systems containing elements of the binder matrix and the active ingredient, with the subsequent removal of water by means of compressed air or vacuum drying.

U.S. patent 5298261 describes bystrotverdeyuschie dosage form, which is partially fused network matrix, which was dried under vacuum at a temperature exceeding the temperature adhesion matrix. However, it is preferable that the matrix is at least partially dried at a temperature below ravnovesnaya dosage forms, which contain a dispersing agent, inducing the formation of bubbles, intended for the formation of bubbles upon contact with saliva, which ensures rapid dissolution of the dosage form and the dispersion of the active ingredient in the oral cavity.

The term "bystrorazvarivayuschayasya dosage form", thus, covers all types of dosage forms described in the previous paragraphs. However, particularly preferably, dosage form constituted such a form, as described in UK patent 1548022, and was solid bistrotdepierrerue dosage form comprising a fiber structure of the dosage form and the water-soluble or vodoroslyami medium that is inert to the active component; a fiber structure obtained by sublimation of the solvent from the composition, in solid form, the composition includes an active ingredient and a solution of the carrier in the solvent.

Preferably, the composition according to the invention was disintegrable for from 1 to 60 seconds, more preferably for from 1 to 30 seconds, especially from 1 to 10 seconds and even more preferably from 2 to 8 seconds when the room is we, as described above, the composition should preferably contain in addition to the active component agents, forming a matrix, and a secondary destination components. Agents, forming a matrix suitable for use in the present invention include compounds - derivatives of animal or vegetable proteins, such as gelatin, dextrins and soy, proteins of wheat seeds and psyllium; gums, such as Arabian gum, guar gum, agar, and xanthan gum; polysaccharides; alginates, carboxymethylcellulose, caragana (drugs of the red algae Chondrus crispus); dextrins; pectins; synthetic polymers such as polyvinylpyrrolidone, and complexes of the polypeptide is a protein or polysaccharide complexes such as gelatin-Arabian gum.

Other agents, forming a matrix suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin, inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate and aminokisloty having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

Components of the secondary purposes, such as preservatives, antioxidants, surfactants, amplifiers viscosity, coloring tools, flavor fragrances, pH modifiers, sweeteners or means of masking the taste, can also be included in the composition. Suitable coloring tools include red, black and yellow iron oxide and FD & C dyes such as FD and C blue 2 and FD and C red 40, supplied Ellis and Everard. Suitable flavoring flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor fragrances, and combinations thereof. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, Solenoe means, masking the taste, include sodium bicarbonate, ion exchange resin, cyclohexanediamine components adsorbed compounds or microencapsulation active compounds.

Preferably, a dopamine agonist was selected from the following compounds: 5,6,6 a, 7-tetrahydro-6-methyl-4H-dibenzo[de, g] quinoline-10,11-diol (apomorphine), 5,6,6 a, 7-tetrahydro-6-propyl-4H-dibenzo-[de,g]quinoline-10,11-diol (N-propylnorapomorphine), (5')-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)ergotaman-3', 6', 18-Trion (parlodel), 1-[(6-arelargely-8-yl)carbonyl] -1-[3-(dimethylamino)propyl] -3-utilmately (cabergoline), N'-[(8)-9,10-didehydro-6-methylergoline-8-yl] -N, N-dieselmachine (lisuride), [[(8)-1,6-dimethylarginine-8-yl] methyl] fenilmetilovy ether of carbamino acid (metergoline), (4aR)-TRANS-and 3,4,4, 5,6,10 b-hexahydro-4-propyl-2H-naphthas[1,2-b] 1,4-oxazin-9-ol (nakagome), 8-[(methylthio)methyl]-6-propylalanine (pergolid), 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinil]pyrimidine (piribedil), 4-[2-(dipropylamino)ethyl] indolin-2-he (ropinirole), N,N-diethyl-N'-[(8)-6-methylergoline-8-yl] urea (argued) and ()-N,N-diethyl-N'-[(3R, 4aR*, 10aS*)-1,2,3,4,4 and,5,10,10 and octahydro-6-hydroxy-1-propellent[g]quinoline-3-yl] sulphonamide (chinagrid), their salts and mixtures thereof. More preferably, the dopamine agonist b is positive, to a dopamine agonist is present in the composition in an amount of from 0.05 to 100 mg, preferably from 0.05 to 20 mg.

The exact amount of active ingredient will depend on your choice of a dopamine agonist. Preferably, the size of the daily dose dopamine agonists listed above, fluctuated within the limits shown in the table.1.

If required the introduction of a large daily dose, it can be introduced in several stages in smaller doses.

As noted above, the dopamine agonists may cause side effects such as nausea and vomiting. Therefore, it is preferable that the composition of the invention was administered in combination with AntiRootkit means. Antervasna tool easier to enter in the same composition, as a dopamine agonist. In one of the preferred options the composition of the invention, as noted above, the optionally included antervasna tool. In the opposite case antervasna tool may be introduced separately from the dopamine agonist with any oral or parenteral routes of administration, for example tablets, capsules, suspensions, suppositories, infusions, injections and so on, at the appropriate time, i.e. before, after or simultaneously with despergiruemaya dosage forms by type, described above, where it was considered that such bystrorazvarivayuschayasya dosage form antivoltage money really has many advantages associated with producing such compositions, which allow to increase the bioavailability, reduce the dose, to facilitate the introduction and so on, as described above, although the specific benefits will depend on the nature of the selected antiemetic.

Preferably, an antiemetic was present in the composition in an amount of from 1 to 120 mg, more preferably 1-60 mg, However, the exact number of anti-emetics, which must be administered to the patient will depend on the selected option. Suitable internatnye tools include peripheral dopamine antagonists, such as 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazole-1-yl)propyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2-he (domperidone) and its salts, as well as receptor antagonists of serotonin (5-HT3), such as endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-lH-indazol-3-carboxamid (granisetron), 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-one (ondansetron), and 1H,5H-tropan-3-Jindal-3-carboxylate (tropisetron) and svodnyh funds noted above, varies in the intervals given in the table.2).

If required the introduction of a large daily dose, it can be introduced in several stages in smaller doses.

Apomorphine is an opium alkaloid. Thus, as noted above, when apomorphine or other alkaloid of opium or its synthetic derivative selected as a dopamine agonist, additional side effects, such as sedation, respiratory depression, hypotension, bradycardia, sweating and yawning, will be observed in addition to nausea and vomiting. However, it was found that all these side effects can be compensated by the introduction of the opioid antagonist in combination with an opioid agonist of dopamine. Opioid antagonist is more convenient to enter in the same composition, as a dopamine agonist. Thus, in another preferred embodiment, the composition of the invention, as noted above, further comprises an opioid antagonist. This composition may also include antervasna tool as an addition to the dopamine agonist and the opioid antagonist, although this is not essential since the opioid antagonist also counteracts some of the effects of a dopamine agonist, causing R is moral or parenteral routes of administration at the appropriate time, that is, before, after or simultaneously with the introduction of a dopamine agonist. Particularly preferably, the composition of the opioid antagonist were made in the form of bistrotdepierrerue dosage forms according to the type described above, where it was considered that such bystrorazvarivayuschayasya dosage form of an opioid antagonist actually has a lot of advantages associated with producing such compositions, which allow to increase the bioavailability, reduce the dose, to facilitate the introduction and so on, as described above, although the specific identified benefits will depend on the nature of the selected opioid antagonist.

Preferably, the opioid antagonist is present in the composition in an amount of from 0.5 to 100 mg, more preferably from 0.5 to 50 mg, However, the exact amount of the opioid antagonist, administered to a patient will depend on the selected type of opioid antagonist. Suitable opioid antagonists include 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-he (naloxone) and 17(cyclopropylmethyl)-4,5-epoxy-3,14-digidroksimorfinan-6-he (naltrexone) and their salts, especially acid salts, especially their hydrochloride. The preferred limits daily dose of naloxone ostatsya the introduction of a large daily dose, it can be introduced in several stages in smaller doses. In accordance with another variant of the invention, a method for the preparation of any of the pharmaceutical compositions of the invention, as described above, which includes creating a connection carrier with active component and/or AntiRootkit means, and/or opioid antagonist.

In another embodiment of the invention it is proposed to use bistrotdepierrerue dosage form intended for quick release of the active ingredient in the oral cavity to accelerate the receipt of a dopamine agonist. The method of injection of a dopamine agonist to a patient, which involves placing the composition in the oral cavity of the patient, as described above.

As noted above, the composition of the invention can be used for combating manifestations of Parkinson's disease. Accordingly, the invention also features a composition, as mentioned above, for the treatment of Parkinson's disease. It is also proposed a method for the treatment of Parkinson's disease, which comprises introducing into the oral cavity of the patient a therapeutically effective amount of the composition, as indicated above.

In addition, AG in patients with Parkinson's disease. Accordingly, the invention further provides a composition, as mentioned above, to assess the severity of Parkinson's disease. It is also proposed a method to assess the severity of Parkinson's disease, which comprises introducing into the oral cavity of the patient a certain amount of a composition as previously discussed, determining the severity of clinical benefit in this patient.

In another embodiment, the invention provides the use of compositions as indicated earlier, for the production of medicaments for treatment and/or assess the severity of Parkinson's disease.

As noted earlier, found that the dopamine agonist may be administered in combination in AntiRootkit means and/or the opioid antagonist according to the available evidence, but antervasna tool and/or the opioid antagonist may be administered in various ways, and individual components can be entered in a different sequence. In accordance with another variant of the invention features a kit for joint injection of a composition comprising a dopamine agonist, as mentioned previously, and antervasna tool and/or an opioid antagonist. For example, the set is accordance with the invention, at least one dosage form antivoltage means and, if the dopamine agonist is an alkaloid of opium, at least one dosage form of an opioid antagonist with instructions for the introduction of this dose of the dosage form. In the preferred form of the set antervasna product is administered prior to administration of a dopamine agonist. To facilitate the introduction of more preferable to antervasna tool and an opioid antagonist, if present, was provided in the form bystrotverdeyushchie dosage forms of the type described above. Accordingly, the kit can include a combination of bystrotverdeyushchie dosage forms, as previously indicated, preferably with instructions on the sequence of their introduction. In a particularly preferred form, the kit may include blister packaging containing the dosage forms of the composition, as previously indicated. Preferably, the sequence of the introduction of the specified dosage dosage forms described in blister packaging. Particularly preferably, when the set includes bystrotverdeyuschie dosage forms containing apomorphine and domperidone and/or naloxon.

In accordance a funds and/or opioid antagonist to a patient, which includes the introduction in the oral cavity of the patient a composition containing a dopamine agonist, as mentioned previously, and the introduction antivoltage funds and/or opioid antagonist to a patient either orally or parenteral. Preferably, antervasna tool and an opioid antagonist, if present, was also provided in the form of bystrotverdeyushchie dosage forms of the type described above, either alone or in combination with a dopamine agonist, which can also be introduced into the oral cavity of the patient.

Further, the invention is illustrated by the following examples.

Example 1. Preparation bistrotdepierrerue dosage forms of apomorphine.

(a) Preparation of 2% dispergiruyushchei composition of apomorphine hydrochloride.

Gelatin (792 g) and mannitol (594 g) was dispersively in a portion of purified water (16 kg) by gently mixing in the tank of the vacuum mixer. The mixture then was heated to 402oC and homogenized in ten minutes. The mixture was cooled to room temperature (20-24oC). After cooling, was added apomorphine hydrochloride (360 g). The mixture is homogenized, providing for the dissolution of drugs. Gradually with stirring EXT is spruce and the volume of the mixture homogenized to achieve complete dissolution.

(b) Preparation of 10-milligramme doses of apomorphine hydrochloride.

500 mg 2% dispergiruyushchei composition of apomorphine hydrochloride, formed after the procedure (a), see above, was Packed up in each of a series prepared in advance blisters placed into the wells with a diameter of 16 mm Shell blisters consisted of 200 micron PVC (polyvinyl chloride) coated with PVdC (polyvinylchloride) at a rate of 40 g per square meter. The product was immediately frozen in liquid nitrogen jar. The frozen product was stored at temperatures below -20oWith at least 12 hours before drying from the frozen state using freeze-drying at the drying temperature +10oC and a chamber pressure of 50 n/m2. Frozen dry unit doses were then examined for the presence of dangerous defects and the remaining portions of this party hermetically Packed with foil coating consisting of a layer of paper and foil (20 μm aluminum). For blister packaging of each unit dose then put the batch number and Packed in a bag of pre-cooked by putting him in a bag and full seal the open end of the bag. Each bag is then indicated the product number, the number S="ptx2">

Example 2. A comparative pharmacokinetic study.

The purpose of this study was to compare the bioavailability of apomorphine hydrochloride after its injection or oral route in the form of bistrotdepierrerue dosage forms prepared according to the method shown in example 1, or the introduction of commercially available composition by subcutaneous injection (subcutaneous) 12 healthy volunteers. Conducted an open, randomized, comparative, 5-factor crossover pharmacokinetic study.

Because of the properties of apomorphine to induce vomiting subjects had previously received domperidone as an antiemetic. After preliminary acceptance of domperidone in 2 days random group of subjects received the following types of treatment with apomorphine in the next 5 days:

5 mg of apomorphine (half unit dose from example 1),

10 mg of apomorphine (unit dose from example 1),

20 mg of apomorphine (two unit doses of example 1, is introduced at the same time)

2.5 mg subcutaneous injection (Britaject) of apomorphine into the wall of the peritoneum,

10 mg of apomorphine (one unit dose of example 1) with the following then after 5 minutes additional introduction

what was harvested prior to the introduction of dose and 6-hour intervals after administration of each dose of apomorphine.

Assessment of the bioavailability of apomorphine was performed using pharmacokinetic parameter AUC (area, reflecting the curve of dependence of the concentration of apomorphine plasma from time to time).

Doses of 5 mg, 10 mg and 20 mg of example 1 caused a dose-dependent increase in bioavailability of apomorphine, estimated using AUC (see table. 4). In addition, the receipt of two 10-milligramme doses with an interval of five minutes caused an increase bioavailability, greater than that in a single dose of 20 mg (see Fig.1).

Example 2 shows that the total absorption of apomorphine with the introduction of it in the form of bystrorasshiryayuscheysya dosage forms increased when the dose of 20 mg was administered as two portions 10 mg with an interval of five minutes, compared with the simultaneous introduction of two portions of 10 mg. it is Assumed that the observed increase in absorption may be due to the action of the composition on the pH of the saliva of the mouth, in which the drug must dissolve before will happen registraciya absorption.

Apomorphine is a drug with properties of the base, which, as is well known, exhibits optimum chemical stability in acidic environment. In this regard, the composition is to create maximum chemical stability. It is possible that these fillers could cause a decrease in the pH of saliva, which can affect the absorption of medications. Surprisingly, this effect can be minimized by introducing another dose after a certain period of time.

In accordance with another variant of the invention, therefore, it is proposed pharmaceutical product comprising a therapeutic dose of a pharmaceutical composition containing a dopamine agonist, as mentioned earlier, in which a therapeutic dose of a composition divided into at least two portions, and pharmaceutical product further includes instructions that recommend consistently to introduce at least two portions with a certain time lag between the introduction of each portion.

The invention also provides a method of injection to the patient a pharmaceutical product comprising a therapeutic dose of a pharmaceutical composition containing a dopamine agonist, as noted previously, in which the dose of therapeutic composition is divided into at least two portions, and method of administration which comprises introducing into the oral cavity of the patient sequentially at least two portions with a certain time interval between every individual portion was in the range of from 2 to 15 minutes, more preferably from 5 to 10 minutes. Preferably also to the instructions on the introduction of at least two portions have been described on the package containing these portions. More preferably, at least two portions contained in a blister pack and preferably to fit instructions introduction.

In an additional embodiment, the invention features a kit for administration of a composition containing a dopamine agonist, as described previously, which includes at least first and second labeled unit dosage forms of the composition, and instructions reflecting the timing of the sequential introduction of the designated units of dosage forms.

The invention also provides a method of introducing the patient a composition containing a dopamine agonist, as indicated earlier, including at least a first and a second labeled unit dosage forms of the composition, the method comprises the sequential introduction of said at least first and second labeled unit dosage forms in the oral cavity of the patient in accordance with the designated time sequence.

Preferably, the time sequence is La interval between introduction of the first and second labeled unit dosage forms. Preferably, instructions defining the time interval of the sequential introduction of at least first and second labeled unit dosage forms have been described on the package containing the labeled unit dosage forms. Particularly preferably, labeled unit dosage forms contained in a blister pack. Preferably, in blister pack was placed instructions.

Particularly preferably, a dopamine agonist that is used as a pharmaceutical product or kit, as previously noted, was a apomorphine, N-propylnorapomorphine or their salts. Preferably, each portion of the labeled unit dosage forms contain from 2.5 to 20 mg, more preferably from 5 to 15 mg, especially 10 mg of apomorphine or its salts.

Another aspect of this discovery is that the absorption of apomorphine can be increased by dose in time, when saliva pH can be maintained within normal physiological fluctuations at the time of obtaining the composition of apomorphine by introducing together with antacid composition. This can be either a specially prepared composition, or who is>M, AludroxTM, AsilonTMor RemegelTM. Antacid should react directly with acid filler and prevent the fall in pH of saliva, which, as expected, reduces the final absorption of apomorphine pagestranny Department of the gastrointestinal tract.

In accordance with this aspect of the invention, therefore, it is proposed pharmaceutical product or kit, as mentioned above, which further comprises an antacid.

The invention also provides a method of injection of a dopamine agonist, a pharmaceutical product or designated unit dosage forms containing a dopamine agonist, as mentioned above, the process of co-administration of a dopamine agonist and antivoltage funds and/or opioid antagonist, as noted above, and the method of treatment and/or assessment of the degree of development

Parkinson's disease, as mentioned above, all of which include an additional step of introducing antacid in the oral cavity of the patient. The antacid may be injected immediately before or after, or simultaneously with the introduction of a dopamine agonist.

It is also proposed antacid used to increase registrales absorption of the active component of the composition, tx2">

The purpose of this study was to compare the bioavailability of 10 mg apomorphically after its oral administration as bistrotdepierrerue dosage form (example 1), placed in the mouth and is able to dispel it, and at its conclusion in hard gelatin capsule and swallowing capsules whole. Held open, random, comparative, 2-factor cross-pharmacokinetic study of 6 volunteers.

Because of the presence of the ability of apomorphine to induce vomiting subjects had previously received domperidone as an antiemetic. After two days of receipt of domperidone randomized group of subjects received the following treatment options by apomorphine in the next two days:

10 mg of apomorphine (example 1)

10 mg of apomorphine, encased in a hard gelatin capsule.

Blood samples for pharmacokinetic analysis were collected prior to administration of apomorphine and through a six-hour intervals after each dose of apomorphine.

Assessment of the bioavailability of apomorphine was performed using pharmacokinetic parameter AUC. Dose of 10 mg (example 1) was caused by the profile change of the concentration of apomorphine plasma, kindred ivala when its introduction was significantly reduced profile changes in the concentration of apomorphine in the plasma. It is clearly apparent change pharmacokinetic parameter AUC, which indicates a significant decrease of the absorption in the group treated with encapsulated apomorphine (see tab. 5).

These results confirm the assumption that apomorphine absorbed preguntarle when entering it in the oral cavity in the form bistrotdepierrerue dosage form of example 1, as when the same composition is injected encapsulated (which should prevent her registernow absorption), the number of apomorphine-defined plasma becomes significantly lower.

The following examples additionally illustrate compositions which can be prepared using the process described in example 1.

Example 4 (see table. 6).

Example 5 (see tab. 7).

Example 6 (see tab. 8).

Example 7 (see tab. 9).

Example 8 (see table. 10).

Example 9 (see tab. 11).

Example 10 (see tab. 12).

Example 11 (see tab. 13).

Example 12 (see tab. 14).

Example 13 (see tab. 15).

Example 14 (see tab. 16).

Example 15 (see tab. 17).

1. Bystrorazvarivayuschayasya farmacevtichnaasociaciya fact, the composition comprises an active component in fiber form and a water-soluble or water dispersible carrier, inert to the active component.

2. The composition according to p. 1, characterized in that the composition desintegrated for from 1 to 60 s after the introduction of the oral cavity.

3. Composition according to any one of the preceding paragraphs, wherein the dopamine agonist is apomorphine or its salt.

4. Composition according to any one of the preceding paragraphs, characterized in that the active component is present in an amount of from 0.05 to 100 mg

5. Composition according to any one of the preceding paragraphs, characterized in that it further includes antervasna tool.

6. The composition according to p. 5, characterized in that antervasna tool is present in an amount of from 1 to 120 mg.

7. Composition according to any one of paragraphs. 3-6, characterized in that it further comprises an opioid antagonist.

8. The composition according to p. 7, wherein the opioid antagonist is present in an amount of from 0.5 to 100 mg

9. Composition according to any one of the preceding paragraphs, characterized in that is used in the treatment of Parkinson's disease.

10. HDMI is S="ptx2">

11. A method of obtaining a pharmaceutical composition according to any of the preceding paragraphs, which includes the interaction of the carrier with active component is a dopamine agonist and, optionally, with AntiRootkit means and, where appropriate, with the opioid antagonist, and by sublimation of the solvent composition in the solid state gain fiber form.

12. The kit includes a therapeutic dose of the pharmaceutical composition according to any one of paragraphs. 1-8, in which a therapeutic dose of a composition divided into at least two portions and the kit further includes instructions for sequential introduction of said at least two portions with a certain time interval between the introduction of each portion.

13. Set for the introduction of the compositions of PP. 1-8, which includes at least first and second labeled unit dosage forms of the indicated composition and instructions that define the time intervals for successive introduction of these at least first and second labeled unit dosage forms.

14. Set for joint injection composition according to any one of paragraphs. 1-4 and antivoltage funds and/or opioid antagonisti in accordance with p. 14, characterized in that it includes a combination of various compositions, as specified in any of paragraphs. 1-8.

16. Set under item 14 or 15, characterized in that it includes a blister pack containing labeled unit dosage forms of the compositions as defined in any of paragraphs. 1-8.

17. Set according to any one of paragraphs. 12-16, characterized in that it further includes antacid agent.

18. The method of administration of a dopamine agonist to a patient, which includes the introduction in the oral cavity of a patient a composition according to any one of paragraphs. 1-4.

19. Route of administration of the pharmaceutical composition, including the introduction of a therapeutic dose of the pharmaceutical composition according to any one of paragraphs. 1-8, in which the specified therapeutic dose of the composition are divided into at least two portions, including the progressive introduction of these portions in the oral cavity intervals of time between the introduction of each portion.

20. Route of administration of the pharmaceutical composition, including the introduction of a therapeutic dose of the pharmaceutical composition according to any one of paragraphs. 1-8, in which the specified therapeutic dose of the composition are divided into at least first and second unit dosage forms listed is denoted by a unit dosage forms in the oral cavity of the patient in accordance with a specific time sequence.

21. The process of co-administration of a dopamine agonist and antivoltage funds and/or opioid antagonist to a patient, which comprises introducing into the oral cavity of a patient a composition according to any one of paragraphs. 1-4 and the introduction antivoltage funds and/or opioid antagonist to a patient either orally or parenteral.

22. The method according to p. 21, characterized in that it includes an introduction into the oral cavity of a patient a composition according to any one of paragraphs. 1-8.

23. A method of treating Parkinson's disease, which comprises introducing into the oral cavity of the patient a therapeutically effective amount of a composition according to any one of paragraphs. 1-8.

24. A method of evaluating the degree of development of Parkinson's disease, which comprises introducing into the oral cavity of the patient selected amount of a composition according to any one of paragraphs. 1-8 and determining the clinical effect of the specified composition in a given patient.

25. The method according to any of paragraphs. 18-24, characterized in that it comprises the additional step of introducing antacid in the oral cavity of the patient.

26. Antacids tool used to increase registrales absorption of the active component of the composition in accordance with any of paragraphs. 1-8.

 

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