Initial anticonvulsant compositions and a method for administering anticonvulsant agents

FIELD: neurological diseases.

SUBSTANCE: composition contains therapeutically effective amount of anticonvulsant agent dissolved or dispersed in aqueous carrier containing 10-80 vol % aliphatic alcohol, 10-80 vol % ethylene glycol, and 0.1-5 vol % bile acid salt or lecithin. Indicated carrier ensures increased access of anticonvulsant agent (such as benzodiazepin, in particular diazepam, clonazepam, phoenitoin, mephoenitoin, ethotoin, phenobarbital, carbamazepin, ethosuccinamide, valproic acid, gabapentine, trimethadion, lamotrigin) into blood and rapid pharmacological response when using nasal administration.

EFFECT: accelerated anticonvulsant effect.

11 cl, 9 dwg, 10 tbl, 13 ex

 

The SCOPE TO WHICH the INVENTION RELATES.

This invention relates to pharmaceutical compositions for the delivery of biologically active agents through the mucous membrane. More specifically, this invention relates to a new method of regulation and stimulate the rate and degree of penetration through the mucosa and suction anticonvulsant agent in a joint application of the medicinal product with a pharmaceutically acceptable cosolvent system comprising an aliphatic alcohol, a glycol and water and their combination with biological surfactants such as salts of bile acids or lecithin. More specifically, this invention relates to pharmaceutical compositions that create acceptable to the patient nasal delivery system anti-convulsants, which is applicable for emergency assistance in the case of continuous epileptic seizure (status epilepticus) and attack of fever and rapid and convenient method of application.

BACKGROUND of INVENTION

Status epilepticus (continuous epileptic seizure) is a critical neurological condition in which mortality is 3-35%. The main aim of treatment is the rapid elimination of the activity of a pathological attack; the later will begin treatment this is estopa, the harder it is to control and the greater the risk of chronic cerebral disorders. Therefore, decisive for the care the patient is a clear programme of action, including rapid treatment effective drugs in adequate doses in an appropriate pharmaceutical formulation, and hypoventilation (lung) and sterile hypotension.

Currently, the treatment status epilepticus used several schemes taking medicine. Diazepam and lorazepam are the most widely used benzodiazepines for this purpose. Intravenous protivosudorozhnyh funds is the fastest way to suppress epileptic seizures. However, other methods of application can be very desirable when intravenous administration is inconvenient and delayed, for example, due to technical difficulties such as the need for sterile equipment and experienced staff and because of the possible development of thrombophlebitis. In addition, intravenous therapies are often associated with hypotension, cardiac arrhythmia or weakening of the functions of the Central nervous system. In this regard, Moolenaar [Moolenaar et al., Int. J. Pharm., 5:127-137 (1986)] have tried to introduce diazepam patients in several other ways, such as intramuscular injection, oral tablet, rectal solution. It was found that only rectal administration ensures rapid absorption and therefore, can be considered as an alternative IV (I.V) injection. However, the rectal route is very inconvenient method of administration of a drug, especially in the case of emergency. In U.S. Patent 4863720 (Burghardt) describes sublingual, injectable pharmaceutical preparation in which the active drug substance may be benzodiazepine, optimally containing polyethylene glycol (PEG, PEG) and ethanol, di - and/or triglycerides of fatty acids and pharmaceutically acceptable gas propellant is used.

Later it was found that the introduction through the mucous membrane of the nose provides a therapeutic effect in the case of many drugs. Nasal application has the advantage that the medicinal substance can be entered easily and simply to achieve a systemic or local effect. However, the main problem when taking medicinal substance through the nose is the fact that most of the molecules of medicinal substances slowly and weakly diffuse through the mucous membrane of the nose and, therefore, specified levels of therapeutic agent can not be achieved with a simple introduction through the nose. An additional limitation related to nazalnam introduction is required for the introduction of a small volume; it is usually not possible to enter into each nostril over 150 µl; the excess goes into the throat and swallows who I am. Therefore, the required solvent-carriers with high solubility in medicinal substances and not irritating the mucous membrane of the nose. Absorption of drugs through the nose can be increased by the joint introduction of a chemical adjuvant or permeability enhancers. For example, Lau and Slattery [Lau et al., Int. J. Pharm., 54:171-174 (1989)] was trying to enter a benzodiazepine, such as diazepam and lorazepam, dissolving these medicinal substances in several solvents: triacetin, dimethyl sulfoxide, PEG 400, Cremophor EL, Lipal-9-LA, isopropylidene and Azone (Azone). Although many of the solvents was dissolved diazepam and lorazepam in the right concentrations, they cause severe irritation to enter in the nose. Found that Cremophor EL (cremophor) less all irritate the nose. But nasal suction when using this media people slow enough (Tmax=1.4 hours) and the maximum concentration is low compared to the concentration observed after intravenous administration. In U.S. Patent 4950664 Rugby describes nasal introduction benzodiazepine sleeping pills in a pharmaceutically acceptable carrier. The carrier may be water, saline, alcohol, a glycol, a simple ether glycol or mixtures thereof. The results of pharmacokinetic studies in dogs showed that the time after which the concentration of triazolam in the plasma temperature is t maximum is 18 minutes after nasal administration, although the objective is urgent help within 5 minutes. Bechgaard and Hjortkjer [Bechgaard et al., J. Pharm. Pharmacol., 49: 747-750 (1997)] have described the use of pure organic solvents, such as glucotrol and tetraethylene glycol, and combinations of them as carriers for nasal delivery of diazepam. Absolute biocompatibility, measured during the first 30 minutes after insertion through the nose, was 49-62% for the most promising of the studied systems media. In PCT application WO 95/31217 Dumex has described the use of a pharmaceutical preparation in the form of emulsion-based tocopherol and its derivatives for nasal administration of biologically active compounds, including benzodiazepines.

The INVENTION

This invention covers a new way modulated using solvent injection anticonvulsant agent through the mucous membranes of humans and animals. The system solvent is aqueous pharmaceutical carrier containing an aliphatic alcohol or glycol and their combinations with biological surface-active substance, such as salt of the bile acid or lecithin.

The purpose of this invention is to provide a pharmaceutically acceptable system of carriers, which can increase the penetration and absorption through the mucous membrane anticonvulsant AG the NTA. The ingredients used in pharmaceutical compositions, preferably consist of a GRAS (generally recognized as safe) substances, so that the question of toxicity is not worth it. Another purpose of this invention is to provide a method for controlling delivery of anticonvulsant substances through the mucous membrane with appropriately adjust the speed so as to achieve an optimal therapeutic effect and to avoid or reduce unwanted side effects. Such compositions are especially applicable for the introduction of drugs through the nose for urgent assistance in the case of the status of epilepticus and bouts of fever.

BRIEF DESCRIPTION of FIGURES

Figure 1 shows a graph showing the effect of filler on the in vitro penetration of the drug diazepam according to the invention through the mucous membrane of the nose.

Figure 2 is a graph showing the effect of the drug concentration on the in vitro penetration of the drug diazepam of the media according to the invention through the mucous membrane of the nose.

Figure 3 shows a graph showing the influence glycocholate sodium (SGC) on the in vitro penetration of the drug diazepam of the media according to the invention through the mucous membrane of the nose.

4 are curves the average concentration of diazepam of time after intravenous (I.V, IV infusion and intranet the form of further administration of the drug according to this invention (a single dose).

Figure 5 is given curves the average concentration of diazepam in plasma of time after intravenous and intranasal administration of the drug according to the invention (multiple dose).

Figure 6 is given curves the average concentration of diazepam in plasma - time after intranasal administration of the drug as a function of the volume ratio of the polyethylene glycol, ethanol in the preparation according to the invention.

7 are curves of the average concentration of clonazepam in plasma of time after intravenous and intranasal administration of the drug according to the invention (single and multiple dose).

On Fig given curves: the average concentration of (S)-2-carbamoylated-1-o-chlorophenylalanine plasma - time after intravenous and intranasal administration of the drug according to the invention as a function of dose.

Figure 9 is given curves: the average concentration of (S)-2-carbamoylated-1-o-chlorophenylalanine plasma - time after intravenous and intranasal administration of the drug according to the invention (single and multiple dose).

DETAILED description of the INVENTION

According to this invention certain water-cosolvent system containing one aliphatic alcohol, one glycol and biological surfactant, provides improved regulation of speed, transnasal delivery of the anti-Christ. dorozhnogo agent. The alcohol in this invention are selected from C1-C5-aliphatic alcohols; glycol selected from propylene glycol (PG), polyethylene glycol (PEG, PEG) 200, PEG 300 and PEG 400 and PEG 600; and biological surfactant selected from salts of bile acids, such as Holt sodium, sodium deoxycholate, taurocholate sodium, glycocholate sodium and ursodesoxycholic sodium, or lecithin, such as lysophosphatidylcholine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and phosphatidylglycerol. The above composition can be applied to pharmaceutical preparations containing anticonvulsant substances suitable for the mucous membranes of humans and animals. More specifically, these drugs are compositions that contain a benzodiazepine, such as diazepam, clonazepam and lorazepam, and new anticonvulsant compound based on monocarbonate, (S)-2-carbamoylated-1-o-chlorpheniramine, represented by the following formula:

adapted for insertion through the nose, in solution, suspension, gel, or another applicable for nasal injection of the formulation. These nasal compositions can be applied to any of the known therapeutic purposes, which are known anti-convulsants, including phenytoin (phenytoin, mean coin and ethotoin), barbiturates (phenobarbital, mephobarbital and primidone), iminostilbene (carbamazepine), suktinimida (ethosuximide), valproate acid, oxazolidinedione (trimethadione) and other anti-epileptic seizures (gabapentin, lamotrigine, acetazolamide, felbamate and γ-vinyl GABA). The use of intranasal formulations anticonvulsant substances greatly facilitates the application. Compared with parenteral introduction, for example, a simple spray or inhaler sufficient for fast and convenient drug delivery, in particular for fast relief of acute attack of epilepsy. From a clinical point of view intranasal introduction often leads to a more prolonged anticonvulsant effect. According to this invention, therapeutic effect, from the point of view of attack, intensity, and duration can more efficiently and accurately adjusted by changing the ratio of the aliphatic alcohol and glycol in the media and by introducing in the form of single or multiple doses of the drug according to the invention. Although this invention is described with regard to the anticonvulsant substances as model compounds, it is clear that this invention is also applicable to other biologically active substances that are applicable to the mucous membranes of humans and animals.

The invention is further illustrated with edowski examples which only illustrate a particular way of practical application of the invention and do not limit the scope of the invention.

Example 1

In vitro study of penetration (passing) through the nasal membrane

The mucous membrane of the nose, used in these in vitro experiments, receive from new Zealand white rabbits (2.5 to 3.0 kg). Rabbits kill using (IV) (IV) injection of phenobarbital. Nasal septum carefully separated from the bone using surgical scissors and saws for cutting bones. Then two pieces (two pieces) of the mucous membrane of the nose gently clean off (separated from) the walls, without touching the center of the surface membrane and washed with normal saline solution. The mucous membrane is placed between the two halves of the camera glass device (camera) to study diffusion. The exposed surface is approximately 0,64 cm2. The test solution or suspension (3.5 ml) is injected from the side of the mucosal membrane in the donor compartment, whereas in 3.5 ml of 10% ethanol, 40% glycol and 50% isotonic phosphate buffer pH 7.4 injected into the receptor compartment. All diffusion system incubated at 37°during the whole experiment. Intervals 100 μl of receptor solution taken for analysis and again filled with the same volume of p is capturei environment, keeping the volume constant. The amount of the transfer in the stationary state is determined by the slope of the straight line on the graph of the cumulative number of past drug substances depending on time. Each experiment is carried out at least twice. This method is used in Examples 2-6.

This study used the system for liquid chromatography high pressure system code several (mixtures) solvents (Model 600E, Waters Associates, Milford, Mass), with automatic syringe (AVTODOM) (Model 717 Plus, Waters Ass.), a detector in the form of a set of photodiodes (Model 996 Plus, Waters Ass.), reversed-phase column Symmetric C18(150 mm × 3.9 mm ID, 5 μm) and a computer system with software Millenium 2010. Mobile phase and UV wavelengths used for the analysis of diazepam, clonazepam and (S)-2-carbamoylated-1-o-chlorophenylalanine, it is 70% methanol, 30% water at 254 nm; 60% methanol, 40% water at 252 nm; and 25% acetonitrile and 75% water at 262 nm, respectively.

Example 2

This example shows the influence of the salts of the bile acids and lecithin dissolved in an aqueous medium with a concentration of 1% weight/volume on the in vitro penetration model drug substance diazepam through svezheispechennomu nasal membrane. In these studies investigate a range of bile salts, such as Holt sodium, sodium deoxycholate, taurocholate sodium and glycocholate on the matter, and lecithin, such as lysophosphatidylcholine. The permeation rate is measured using the method described in the in vitro penetration through the nasal membrane. Average data transnasal transfer in the steady state, thus obtained, are presented in Table I.

As can be seen from Table I, the salt, the bile acids, such as glycocholate sodium, lecithin, such as lysophosphatidylcholine, have a significant impact on the passage of diazepam through the mucous membrane (the membrane) of the nose.

Example 3

This example illustrates the influence of media on in vitro passage of diazepam through the mucous membrane of the nose of the rabbit at 37°C. In this experiment, a 1% suspension and the solution of diazepam is prepared using water and media from co-solvents consisting of 30% ethanol (EtOH), 60% propylene glycol (PG) and 10% water (WT), respectively. The permeation rate is determined according to the method described in Example 1. Graphics transnasal passage (penetration), thus obtained, is shown in figure 1.

As can be seen from Figure 1, the carrier of co-solvents containing ethanol, propylene glycol and water, contributes almost 8-fold increase in the speed transnasal transfer of diazepam compared to the speed of the water suspension.

Example 4

This example shows the effect to which ncentratio medicinal substance in the donor half (compartment) to the passage (transport) diazepam through the mucous membrane (the membrane) of the nose in vitro. In this study, prepared at 0.5-2% drugs diazepam, using a mixture of co-solvents, containing 30% ethanol, 60% propylene glycol and 10% water. Speed in vitro transmembrane transport (pass) is determined according to the method described in Example 1. Data transnasal migration in vitro, obtained at concentrations of diazepam in the formulations of 0.5-2%, shown in figure 2.

As can be seen from Figure 2, transnasal the transfer of diazepam in the steady state increases linearly with increasing the drug concentration in the donor half above 0,5-2,0%.

Example 5

This example illustrates the effect of introducing a salt of bile acid in nasal formulation according to the invention for in vitro passage of diazepam through the mucous membrane of the nose. In this experiment studied the effect of introducing 1% glycocholate sodium in a medium consisting of 30% ethanol, 60% propylene glycol and 10% water. Prepare sample solutions of medicinal substance (10 mg/ml) in media containing and not containing salt, the bile acids. The speed of transport through the membrane is measured according to the method described in Example 1. Graphics in vitro penetration (transport), thus obtained, are presented in figure 3.

As can be seen from Figure 1, the introduction of 1% glycocholate sodium significantly increases the speed of diazepam through the mucous membrane of the nose. Noted almost 50%enhancement the transmembrane transfer in a stationary state, when the carrier salt of bile acid.

Example 6

This example illustrates the comparative transnasal permeability of the three model drugs, such as diazepam, clonazepam and (S)-2-carbamoylated-1-o-chlorpheniramine. In this experiment, using the media of co-solvents consisting of 30% ethanol, 60% propylene glycol and 10% water. In vitro experiments on the penetration (passing through) carried out using the analysis method described in Example 1. Comparative permeability through the membrane and data transfer in the steady state obtained for drugs with an initial concentration of drugs 5 mg/ml, presented in Table II.

Table II
Comparative transnasal permeability of the three model drugs across rabbit nasal mucosa In vitro
Drug connectionThe permeability coefficient (cm/hour)Transnasal transfer (µg/cm2/hour)
Diazepam4,92×10-2246,0
Clonazepam6,95×10-2347,7
(S)-2-carbamoylated-1-o-chlorpheniramine 9,77×10-2487,6

As can be seen from Table II, transnasal permeability anticonvulsant substances on the basis of monocarbonate, (S)-2-carbamoylated-1-o-chlorophenylalanine, apparently, twice transnasal permeability of diazepam.

Example 7

Bioavailability and pharmacokinetics of drugs diazepam

Characteristics of bioavailability and pharmacokinetics of drugs according to the invention, containing diazepam, define (analyze) after nasal introduction of new Zealand white rabbits (n=3-4). For comparison, examine the effect of injections of diazepam (Formula 1 in Table III) in vivo after intravenous injection of the same dose. Centuries of Formula 1 (10 mg/2 ml) obtained from Elkins-Sinn, Inc., they are prepared with propylene glycol (0.4 ml), ethanol (0.1 ml), benzyl alcohol (0,015 ml), sodium benzoate/benzoic acid (50 mg) and sufficient water for injection to make 1 ml For nasal application serves two drugs, using a system of carriers according to the invention, consisting of 30% ethanol, 60% propylene glycol and 10% water (Equation 3 in Table III) and without (Equation 2 in Table III) 1% glycocholate sodium, respectively. Another recipe for the nose (nasal) (Formula 4 in Table III) with a non-ionic surface-active media, polyoxyethylene castor oil (Cremophor EL) also experience after intranasal what about the application in order to compare, since this drug was tested on human beings Lau and Slattery (1989). All preparations for introduction into the nose prepared immediately before the experiments, dissolving 20 mg of diazepam (Sigma Chemical) in 1 ml of the above media.

Immediately before the experiment rabbits (n=3-4) is weighed and placed in a cage for training. Each rabbit injected with 100 μl of drugs of Formula 2 or 3 in each nostril spray Pfeiffer (Pfeiffer) for 5 sec. Rabbits receiving centuries (IV)administered 1 mg/kg of the drug of formula 1 into the ear vein intravenous infusion for 20 seconds. To study the action of repeated doses of the same amount of the drug of Formula 3 (100 µl) was injected into each nostril 5 minutes after the first dose. Blood samples (1 ml) are taken through 0, 2, 5, 10, 20, 30, 45, 60 and 120 minutes after IV (VV) IN the introduction. From samples of blood plasma is separated by centrifugation and stored at -20°before the test. For the analysis of plasma samples (0.5 ml) carefully transferred into a polypropylene tube for centrifuge 1.5 ml of the plasma sample, add 0.5 ml of 0.01% volume/volume perchloro acid in acetonitrile containing internal standard (clonazepam 1 mg/ml). The mixture is stirred for 30 sec and centrifuged at 4000 rpm for 10 minutes. The concentration of diazepam in plasma analyze HPLC. The analysis is performed using Waters HPLC as described in Example 1. In this study, using a column of 3.8 mm × 15 mm × 5 μm Symmetric C18. The mobile phase 50% vol. methanol:10% vol. acetonitrile:40% vol. phosphate buffer with a pH of 3.5. The velocity of the mobile phase, 1 ml/min and UV detection was performed at 228,5 nm. The detection limit for diazepam is 70 nmol/l Area (AUC) under curves plasma concentration - time from 0 min to 120 min, calculated using the linear trapezoidal method. Data on the bioavailability and pharmacokinetics, thus obtained, are shown in Table III. Comparative pharmacokinetic curves obtained after a single VV (IV) the introduction of (Formula 1) and a single and double IN-injection according to the invention (Formulas 3 and 4, shown in figures 1 and 5, respectively.

Table III
Characteristics of bioavailability and pharmacokinetics of diazepam after IV (VV) and IN (I.N) the drug according to the invention rabbits
Method/ MedicationDose (mg/kg)Cmax(ng/ml)Tmax(min)AUC(0-120 min)(ng × min/ml)F(%)
IV Formula 1a(BB)Single

(1 mg/kg × 1)
398,8 (63,0)d2,017582 (407)d100,0 (n=3)
b(Jn)Single (1 mg/kg × 1)273,6 (62,2)d5,010383 (692)d59,1 (n=3)
IN Formula 3c(Jn)Single (1 mg/kg × 1)273,7 (26,4)d2,013300 (972)d75,7 (n=4)
IN Formula 3c(Jn)Double (1 mg/kg × 2)327,1 (29,7)d2,026787 (972)d76,2c(n=3)
556,9 (130,5)d10,0
IN Formula 4g(Jn)Single (1 mg/kg × 1)73,3 (11,9)d30,07497 (1445)d42,6 (n=3)
andIV (IV) Formula 1: injection of 0.5% diazepam, USP, Elkins-Sinn, Inc., (PG/EtOH/benzyl alcohol/sodium benzoate/benzoic acid/water for injection)

bIN (Jn) Formula 2: 2% solution of diazepam in 60% PG, 30% EtOH and 10% water

withIN (Jn) Formula 3: 2% solution of diazepam in 1% SGC, 60% PG, 30% EtOH and 10% water

dStandard deviation

eNormalized data is defined by the equation:

F={AUCIN,1 mg×2/2 × AUCIV, mg×1/×100}

fTime of application: t0: first up is for nasal injection

t5 minutesthe second dose for nasal injection

gIN (Jn) Formula 4: 2% solution of diazepam in Cremophor EL.

As can be seen from Figure 4 and Table III, IN Formula 3, prepared with 1% SGC, 30% EtOH, 60% PG and 10% water improves the transnasal absorption compared with Cremophor EL Formula 4. Value Withmaxand AUC0-120 minIN Formula 3 is about 69% and 76% relative to the corresponding values for IV injection (IV), respectively. On the other hand, the value Ofmaxand AUC0-120 minfor Cremophor EL Formula 4 is about 19% and 42.6% of the values for IV injection. These relative results seems consistent with the data on the pharmacokinetics of man, published Lau and Slattery (1989). According to published data, Tmaxdrug Cremophor EL is 1.4 hours after intranasal person, but Withmaxis only 27% compared to IV injection. Quite unexpected, as can be seen from Figure 5 and Table III, is that repeated intranasal introduction 5 minutes after the first dose gives a noticeable increase in intranasal absorption of diazepam. Valuesmaxand AUC exactly twice after the second injection compared with the values obtained with the first introduction. In addition, the level of diazepam in plasma after the second dose exceeds the level at single IV for 7 minutes. E and opening clearly demonstrate that scheme repeated dose (for a short period of time) can be used effectively to urgent care with a fit of epilepsy, when a single intranasal dose is not able to provide the desired therapeutic effect.

Example 8

Control of pharmacokinetics at maximum concentrations (peaks) in plasma

Prepare two mg diazepam in 100 μl media and injected rabbits (n=3) as described in Example 7. Have the following drives: 60% EtOH, 30% PG and 10% water (WT) with 1% SGC, 30% EtOH, 60% PG and 10% water (WT) with 1% SGC, and 20% EtOH, 70% PG and 10% water (WT) with 1% SGC. Blood samples taken from the ear vein with the following 5-minute intervals: 0, 2, 5, 10, 20, 30, 45, 60 and 120 minutes. The concentration of diazepam in plasma determined HPLC. Pharmacokinetic curves obtained after IV and IN administration of the drugs presented in Table IV and figure 6.

Table IV
The effect of volume ratio of EtOH/PG in media pharmacokinetic indicator of diazepam after IV and IN administration of the preparation according to the invention rabbits
Method/ MedicationDose (mg/kg)Cmax(ng/ml)Tmax(min)AUC(0-120 min)(ng × min/ml)F(%)
IV Formula 1a(BB)Single

(1 mgkg × 1)
398,8 (63,0)e2,017582 (407)e100,0 (n=3)
IN the Formula Ab(Jn)Single

(1 mg/kg × 1)
313,2 (17,3)e2,013592 (692)e77,3 (n=3)
IN the Formula In thec(Jn)Single

(1 mg/kg × 1)
273,7 (26,4)e2,013300 (972)d75,7 (n=4)
IN the Formula Withd(Jn)Single

(1 mg/kg × 1)
246,3 (32,2)e2,012860 (827)e73,1 (n=3)
andIV (IV) Formula 1: injection of 0.5% diazepam, USP, Elkins-Sinn, Inc., (PG/EtOH/benzyl alcohol/sodium benzoate/benzoic acid/water for injection)

bIN (Jn) Formula: 2% solution of diazepam in 60% PG, 30% EtOH and 10% water

withIN (Jn) Formula: 2% solution of diazepam in 1% SGC, 60% PG, 30% EtOH and 10% water

dIN (in) the Formula: 2% solution of diazepam in 1% SGC, 70% PG, 20% EtOH and 10% water

eThe standard deviation

As can be seen from Table IV and 6, the maximum concentration of drug substance in plasma observed after 2 minutes IN the introduction, can be adjusted depending on the volume ratio of EtOH/PG in the studied media. Withmaxgradually took the scarfing with increasing volume ratio of EtOH/PG from 0.3 to 2. In addition, the maximum concentration in plasma for IN-medium consisting of 60% EtOH, 30% PG and 10% water (WT) with 1% SGC, after 2 minutes is about 79% of the corresponding values at IV injection.

In addition, by modulating the volume ratio of EtOH/PG in media can also be adjusted graph of plasma concentration - time at the stage of elimination.

Example 9

Pharmacological response to a drug diazepam

Pharmacological response study in new Zealand white rabbits, evaluating the influence of diazepam for muscle relaxation after IV (C)-the introduction and IN (in)administration of the preparations according to the invention at the dose level of 1 mg/kg of Carrier nasal drug consists of 30% ethanol, 60% propylene glycol and 10% water containing 1% SGC. Sample preparation is prepared by dissolving 2 mg of diazepam in 1 ml of media using ultrasound. IV-the recipe is the same as the formulation used in Example 7. Pharmacological response measured in rabbits after injection of 100 μl of nasal formulations in each nostril at the position of the rabbit lying, while his thigh firmly pressed his finger. The average response time (reaction), during which the rabbits remain in the supine position, with their hind legs stretched out in one direction, IV (IV) and IN (in) administration, are listed in Table V.

Table V
Average time pharmacological reactions after IV (BB) and IN (in)administration of drugs diazepam
Method/recipeResponse time (min)N
IV (IV)injection1,1±0,23
IN (Jn)-injection1,5±0,53

As can be seen from Table V, nasal preparation according to the invention provides very fast response. Time pharmacological reaction is 1.5 minutes.

Example 10

Bioavailability and pharmacokinetics of drugs clonazepam

Intranasal formulation is prepared by dissolving at 8.36 mg of clonazepam in 2 ml of media according to the invention, consisting of 30% EtOH, 60% PG and 10% water containing 1% SGC. Medicine for centuries (IV)injection is prepared by dissolving 3 mg of clonazepam in 2 ml 40% PG, 30% EtOH and 30% water and filtration through a sterile filter under aseptic conditions. Drugs administered to rabbits (n=3) at a dose of 0.2 mg/kg as described in Example 7. They also examine the scheme with the second (multiple, double, triple) dose of 5-minute intervals. Blood samples taken from the ear vein at the following time points: 0, 2, 5, 10, 20, 30, 45, 60 and 120 minutes. From samples of blood plasma is separated by centrifugation and stored at -20°before the test. For the analysis of plasma samples (0.5 ml) carefully transfer the tubes 1.5 ml The plasma sample add 10 ál of internal standard solution (diazepam 5 mg/ml) and 50 ml of NaOH (0.5 M). To the above mixture add 5 ml of diethyl ether and the mixture is stirred for 60 s and centrifuged at 4000 rpm for 10 minutes. The above ether solution is transferred into a test tube 5 ml and evaporated in a vacuum evaporator at 40°C for 30 min Rest "reproduce"by adding 100 ál of mobile phase for HPLC analysis, consisting of 20% methanol, 30% acetonitrile and 50% buffer solution KN2PO4/N3PO4with a pH of 3.5. The concentration of clonazepam in plasma determined HPLC at a flow rate of 1 ml/min using UV detection at 254 nm. The detection limit for clonazepam is 16 nmol/L. Data on the bioavailability and pharmacokinetics obtained after centuries (IV) and I.N IN introducing a scheme of a single or multiple doses, given in Table VI and graphs of average plasma concentration against time are presented in Fig.7.

Table VI
Indicators of bioavailability and pharmacokinetics of clonazepam after IV (VV) and IN (I.N) injection in rabbits
Method/ MedicationDose (mg/kg)Cmax(ng/ml)Tmax(min)AUC(0-120 min) (ng × min/ml)F(%)
IV Formulaa(BB)Single

(0.2 mg/kg × 1)
104,82,07437,7100,0 (n=2)
IN Formulab(Jn)Single

(0.2 mg/kg × 1)
32,9 (5,9)c2,03356,4 (544,8)c45,1 (n=3)
IN Formulac(Jn)Double

(0.2 mg/kg × 2)
273,7 (5,3)c10,04896,8 (836,6)c32,9d(n=3)
IN Formulad(Jn)Threef< / br>
(0.2 mg/kg × 3)
an 80.2 (21,3)c15,07766,1 (2077,9)c34,8e(n=3)
aIV (IV) Formula: 0,15% solution of clonazepam in 40% PG, 30% EtOH and 30% water

bIN (Jn) Formula: 0,42% solution of clonazepam 1% SGC, 60% PG, 30% EtOH and 10% water

cStandard deviation

dThe normalized data is calculated by the following equation:

F={AUCIN,0.2 mg × 2/2 × AUCIV 0.2 mg×1}×100

eThe normalized data is calculated by the following equation:

F={AUCIN,0.2 mg × 3/3 × AUCIV 0.2 mg×1}×100

fTime: tzero: first dose d is I a nasal injection

t5 minutesthe second dose for nasal injection

t10 minutes: third dose for nasal introduction

As can be seen from Table VI and 7, the first peak plasma concentration occurs within 2 minutes after the first nasal administration of the drug. The maximum plasma level (peak) is 32% from the value at the fourth (IV) injection. However, after the third injection with 5-minute intervals maximum plasma concentration (pic), observed after 15 minutes, almost identical concentrations after a single IV (IV)injection of clonazepam.

Example 11

Pharmacologic response to the drugs clonazepam

Pharmacologic response to the drugs clonazepam study in new Zealand white rabbits after injection of 100 μl 4,18 mg clonazepam/ml of media into each nostril in the same way as in Example 9. The media consists of 30% ethanol, 60% propylene glycol and 10% water containing 1% SGC. Clonazepam is dissolved in the carrier by means of ultrasound. Recipe for IV (IV)injection used in the study, the same as in Example 10. The average response time after IV (BB) and IN (in) the introduction is presented in Table VII.

Table VII
Average time pharmacological response after IV (BB) and IN (Jn)-injection CL is nazepam
Method/recipeResponse time (min)N
IV (IV)injection1,7±0,53
IN (Jn)-injection1,4±0,73

As shown in Table VII, intranasal introduction drug clonazepam according to the invention provides more rapid response (1.4 minutes)than IV (IV)injection (1.7 minutes).

Example 12

Bioavailability and pharmacokinetics of drugs (S)-2-carbamoylated-1-o-chlorophenylalanine

Intranasal formulation is prepared by dissolving 50 mg or 100 mg of a new anticonvulsant agent-based monocarbonate (S)-2-carbamoylated-1-o-chlorophenylalanine in 1 ml of media according to the invention, consisting of 30% EtOH, 60% PG and 10% water containing 1% SGC. Medicine for centuries (IV)injection is prepared by dissolving 15 mg of (S)-2-carbamoylated-1-o-chlorophenylalanine in 1 ml of 40% PEG (PEG) 400 and 60% water and filtering through a sterile membrane under aseptic conditions. Drugs administered to rabbits (n=2-4) in the form of two different doses of 2.5 mg/kg and 5 mg/kg method similar to that described in Example 7. Also study the scheme of multiple (repeated) doses of 5-minute intervals during introduction into the nose of the preparation according to the invention. Blood samples taken from the ear vein at the following time points: 0, 2, 5, 10, 20, 30, 45, 60, 120, 180 and 240 minutes. From samples of blood plasma is separated, zentrifugenbau the m and stored at -20° With before the test. For the analysis of plasma samples (0.5 ml) carefully transferred into a test tube 15 ml of the plasma sample add 50 ál of the internal standard solution (2-(2,6-dichlorophenyl)-2-carbamoyloximes)exacerbated-1 - µg/ml) and 5 ml of motivational ether. The mixture is stirred for 60 s and centrifuged at 3500 rpm for 10 minutes. The above ether solution is transferred into a test tube 5 ml and evaporated in a vacuum evaporator at 40°C for 30 min. Balance of plant ("reproduce") in 200 µl of deionized water. The concentration of (S)-2-carbamoylated-1-o-chlorophenylalanine in plasma determined by HPLC using a mobile phase consisting of 20% acetonitrile and 80% water, at a flow rate of 1 ml/min using UV detection at 210 nm. The detection limit for (S)-2-carbamoylated-1-o-chlorpheniramine is 23 nmol/L. Pharmacokinetic parameters determined after centuries (IV) and I.N IN the introduction (S)-2-carbamoylated-1-o-chlorophenylalanine in the form of two different doses presented in Table VIII. The parameters of bioavailability and pharmacokinetics obtained after centuries (IV) and I.N IN-injection according to the invention according to scheme a single (one-time) and two doses are given in Table IX. Graphs of the average blood concentration - time received after centuries (IV) and I.N IN-injection (S)-2-carbamoylated-1-o-chlorophenylalanine in the form of (p the diagram) of single and double doses presented at Fig and 9.

Table VIII
Pharmacokinetic parameters of (S)-2-carbamoylated-1-o-chlorophenylalanine after a single IV (VV) and IN (I.)-receive two different doses
Method/ MedicationDose (mg/kg)Cmax(ng/ml)Tmax(min)AUC(0-240 min)< / br>
(ng × min/ml)
F(%)
IV Formulaa(BB)5,06267,7 (408,0)d2,0473176 (56105)d100,0 (n=4)
IN Formula 1b(Jn)5,02404,9 (130,0)d30,0373991 (5077)d79,1 (n=3)
IN Formulaa(Jn)2,54179,92,0221291100,0 (n=2)
IN Formula 2c(Jn)2,51407,25,016026972,4 (n=2)
andIV (IV) Formula: 0,15% solution of (S)-2-carbamoylated-1-o-chlorophenylalanine in 40% PEG (PEG) 400 and 60% water

bIN (Jn) Formula 1: 10% solution of (S)-2-carbamoylated-1-o-chlorophenylalanine 1% SGC, 60% PG, 30% EtOH and 10% water

cIN (Jn) Formula 2: 5% solution of (S)-2-carbarnoyl the XI-1-o-chlorophenylalanine 1% SGC, 60% PG, 30% EtOH and 10% water

dThe standard deviation

Table IX
The parameters of bioavailability and pharmacokinetics of (S)-2-carbamoylated-1-o-chlorophenylalanine after IV (VV) and IN (I.N)-injection scheme of the single and double doses
Method/ MedicationDose

(mg/kg)
Cmax(ng/ml)Tmax(min)AUC(0-240 min)< / br>
(ng × min/ml)
F(%)
IV Formulaa(BB)Single

(5 mg/kg × 1)
6267,7 (408,0)c2,0473176 (56105)c100,0 (n=4)
IN Formulab(Jn)Single

(5 mg/kg × 1)
2404,9 (130,0)c30,0373991 (5077)c79,1 (n=3)
IN Formulab(Jn)Twoe< / br>
(5 mg/kg × 2)
4332,3 (979,3)c30,0700475 (1141956)c74,0d(n=3)
andIV (IV) Formula: 0,15% solution of (S)-2-carbamoylated-1-o-chlorophenylalanine in 40% PEG (PEG) 400 and 60% water

bIN (Jn) Formula 1: 10% solution of (S)-2-carbamoylated-1-o-chlorophenylalanine 1% SGC, 60% PG, 30% EtOH and 10% water

cStandard deviation

dThe normalized data is calculated by the following equation:

F={AUCIN,5 mg × 2/2 × AUCIV, 5 mg×1}×100

eTime: tzero: first dose for nasal injection

t5 minutesthe second dose for nasal introduction

As can be seen from Table VIII, after intranasal initial maximum concentration observed within 5-30 minutes, increase proportionally with dose. It was found that the nasal bioavailability of drugs is 73-79% of the bioavailability in IV (IV)injection. The pharmacokinetic results are presented in Table IX and figure 9 clearly indicate that the second introduction nasal drug after 5 minutes after the first dose provides bioavailability, almost identical bioavailability achieved after the first dose. Valuesmaxand AUC0-240 minutessatisfied after the second intranasal. In addition, the concentration of (S)-2-carbamoylated-1-o-chlorophenylalanine in plasma detected after the second dose exceeds the level in the plasma, resulting in a single IV (IV)injection after 30 minutes.

Example 13

The stability studies

In order to optimize the stability of drugs in pharmaceutical compositions Yes the resultant invention are conducting accelerated stability studies at a storage temperature of 37° With over a 10-14-week period. Sample solutions of medicinal substances (0.1 mg/ml) is prepared using a carrier according to the invention, consisting of 30% EtOH, 60% PG and 10% water. Solutions of medicinal substances are stored in a drying Cabinet at 37°C. at regular intervals select 100 μl of the sample and analyzed by HPLC. Data on chemical stability, a certain percentage of the substance presented in Table X.

Table X
Chemical stability of the preparations according to the invention at 37°
The preparation of medicinal substanceStorage time (weeks)% regeneration substance
The drug diazepam0100,0
4100,3
10102,4
14102,6
The drug clonazepam0100,0
4101,7
11100,9
Drug (S)-2-carbamoylated-1-o-chlorophenylalanine0100,0
3 100,2
4of 98.2
998,0
1297,6

1. Pharmaceutical composition for nasal administration, containing a therapeutically effective amount of an anticonvulsant agent, dissolved or dispersed in an aqueous medium containing 10-80 vol.% aliphatic alcohol, 10-80 vol.% glycol and 0.1-5 wt.% salts of bile acids or lecithin.

2. The composition according to claim 1, wherein the anticonvulsant agent is selected from the group consisting of diazepam, clonazepam, lorazepam, phenytoin, mephenytoin, ethotoin, phenobarbital, mephobarbital, primidone, carbamazepine, etosximida, valproic acid, trimethadione, gabapentin, levels of lamotrigine, felbamate, γ-vinyl gamma aminobutyric acid and acetazolamide.

3. The composition according to claim 1, wherein the anticonvulsant agent is monocarbonate anticonvulsant agent (S)-2-carbamoylated-1-o-chlorpheniramine the following formula:

4. The composition according to claim 1, characterized in that the alcohol is an aliphatic alcohol containing 1-5 carbon atoms.

5. The composition according to claim 1, characterized in that the glycol is chosen from the group consisting of propylenglycol is, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600.

6. The composition according to claim 1, characterized in that the salt of the bile acid selected from the group consisting of cholate sodium, desoxycholate sodium, glycocholate sodium, taurocholate sodium and ursodeoxycholate sodium.

7. The composition according to claim 1, wherein the lecithin is selected from the group consisting of lysophosphatidylcholine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine and phosphatidylglycerol.

8. The way to increase penetration in the blood and provide a fast pharmacological response anticonvulsant agent in natalem administered to a mammal, which consists in the introduction of this agent in a therapeutically effective quantity in the system media containing aliphatic alcohol/glycol and 0.1-5 wt.% salts of bile acids or lecithin.

9. The method of claim 8, wherein the anticonvulsant agent is dissolved or dispersed in the system intranasal carrier to cause rapid action and high plasma concentration of drug substance by increasing the volume ratio of aliphatic alcohol/glycol in the media from 0.1 to 8.0.

10. The method of claim 8, wherein the anticonvulsant agent is dissolved or dispersed in the system intranasal novtel is to cause rapid action and prolonged concentration in plasma drug substances by decreasing the volume ratio of aliphatic alcohol/glycol in media ranging from 8.0 to 0.1.

11. The method according to claim 8, characterized in that a pharmaceutical composition comprising an anticonvulsant agent, and the system intranasal carrier injected into the nose of the mammal in an amount effective for the treatment of epileptic or other caused by fever attacks, using regimens single or multiple doses.



 

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