HK1067044A - Novel pharmaceutical composition for administering n-0923 - Google Patents

Description

Novel pharmaceutical composition for N-0923 administration

Brief description of the invention

The present invention relates to pharmaceutical compositions in Depot form (Depot form) for the administration of dopamine agonist N-0923 (Rotigotine).

A preferred embodiment is an anhydrous pharmaceutical preparation which comprises an oily suspension of the active substance N-0923 in solid phase and N-0923.

Finally, the invention also relates to the use of solid N-0923 for the preparation of a medicament which can be heat-sterilized.

Background

N-0923 (Rotigotine; S (-) -2- (N-propyl-N-2-thienylethylamino) -5-hydroxytetraline) is a potent and selective dopamine D2 agonist with therapeutic effect on all disorders associated with dopamine metabolism, such as Parkinson' S disease and Restless Leg disease (Restress Leg). Various trials have been conducted in the past to administer therapeutically relevant amounts of N-0923.

However, tests have shown that the bioavailability after oral dosing is only about 0.5% (Swart and Zeeuw, Pharmazie 47(1992)613) due to the prominent First-Pass effect (First-Pass-Effekts), so that oral administration is not suitable for N-0923.

Furthermore, the substance is rapidly excreted when administered parenterally in aqueous solution (eliminizing). After intravenous administration of an aqueous solution of N-0923 to monkeys, the half-life of N-0923 is 52 minutes (Walters et al, J.Pharmac Sci 83(1994)758), which results in the need for an inappropriately frequent administration of medication to patients during a sustained period of treatment.

Subcutaneous administration of N-0923 in water (5% glucose) also resulted in a very short duration of efficacy, i.e., 60-70 minutes (Belluzzi, Movement Disorders, 9.2(1994) 147).

Thus, there is a need for a non-oral pharmaceutical form of N-0923 by which the frequency of therapeutic administration required can be significantly reduced.

Thus, transdermal delivery systems were developed in the earliest days. WO 94/07468 describes a two-phase matrix which may contain N-0923 as the active substance. WO 99/49852 discloses a single phase matrix for transdermal administration of N-0923.

Transdermal delivery systems, however, are not suitable for all patients and in principle have a series of inherent disadvantages. Many patients have allergic reactions to substances contained in adhesive plasters (pflasten), such as binders, penetration enhancers and polymers.

In addition, the acceptability of plasters with respect to ethnic tradition and ethnic characteristics is very variable.

Finally, the use of transdermal delivery systems is also only limited to adjusting individual dosages.

It is therefore an object of the present invention to provide a further suitable pharmaceutical preparation which is formed from as few components as possible and which avoids the disadvantages of transdermal delivery and oral administration mentioned above, such as low bioavailability, high administration frequency, immunological potential, possible toxicity and poor individual dosability.

The task of the present invention is accomplished by providing for the first time a pharmaceutical formulation of the active substance N-0923 in depot form, which formulation is suitable for continuous release of N-0923 over a period of at least 24 hours.

In a preferred embodiment, the pharmaceutical formulation is an oily suspension, wherein N-0923 is present in solid form.

In another preferred embodiment, the salt of N-0923 is present in crystalline form in an anhydrous formulation and the continuous plasma level over at least 24 hours after administration to a mammal is from 0.2 to 10ng N-0923/ml blood.

Surprisingly, the preparation of the invention, which is prepared very simply, achieves a therapeutically relevant plasma level of N-0923 over 48 hours. Thus, the compositions of the present invention are simple, cost effective to prepare, biodegradable, non-toxic, and have good compatibility.

Furthermore, it is particularly advantageous that the pharmaceutical compositions according to the invention contain only small amounts of auxiliaries which are both characteristic and compatible.

Furthermore, the dosage can easily be adapted to the individual needs, symptoms and physical conditions of the individual patient by individually adjusting the volume applied or the concentration of the active substance.

Thus, the therapeutic compositions of the present invention are particularly suitable for the treatment of diseases with disorders of dopamine metabolism, such as parkinson's disease and tremor leg disorders. The treatment can be carried out not only as monotherapy but also in combination with other active substances.

Finally, it was completely unexpected that N-0923 was stable when N-0923 was present in the pharmaceutical composition of the present invention in a solid state when heated during heat sterilization. In contrast, the dissolved form of N-0923 suffers significant thermal decomposition upon heat sterilization.

Description of the drawings:

FIG. 1 shows the plasma concentrations of 4 different doses of N-0923 administered subcutaneously to rats as an oily crystal suspension. Administered every 48 hours over several weeks. Fig. 1A shows the average measurements after the second application and fig. 1B is the values after the 46 th application.

FIG. 2 shows the plasma concentration of N-0923 after subcutaneous administration to rats at 12.5mg N-0923/kg body weight. Dosing was every 48 hours. The plasma levels at 2, 4, 8, 24, 32 and 48 hours for each animal after the 22 nd application are also given.

FIG. 3 shows the plasma concentrations of N-0923 after 85 administrations of 1mg/kg N-0923 (FIG. 3A) and 4mg/kg N-0923 (FIG. 3B) to monkeys in oily N-0923 crystal suspension.

FIG. 4 shows the relationship between the dose N-0923 administered as an oily crystal suspension and the maximum plasma level after 3 and 85 daily administrations to monkeys.

Detailed Description

The invention relates to a pharmaceutical composition comprising N-0923 as active substance, which is formed as a depot.

In this patent application, the term "depot form" or "depot" means a non-transdermal delivery drug formulation which results in therapeutically effective plasma levels of N-0923 over at least 24 hours after administration to a patient. The plasma concentration of Rotigotine is preferably 0.2-10ng/ml, more preferably 0.3-5ng/ml, and most preferably 0.4-3 ng/ml.

The term "N-0923" means the substance 2- (N-propyl-N-2-thienylethylamino) -5-hydroxytetraline and its pharmaceutically acceptable salts.

The term "N-0923 derivative" means a substituted 2-aminotetralin, as claimed in US patent US 4,564,628.

Examples of depot forms are microparticles or microcapsules; lipid-based nanoparticles; complexes of the active substance with organic or inorganic substances, such as gelatin, polyvinylpyrrolidone, carboxymethylcellulose or polyglutamic acid, or inserts in these organic or inorganic substances; emulsions or suspensions.

Suitable microcapsules or microparticles can be prepared in a manner known per se, for example by microencapsulation or spray drying based on biodegradable polymers such as polylactide (polylactide) -polyglycolide copolymer (PLGA), as described in EP-0625069.

In a preferred embodiment, the depot form is formed as a suspension, preferably as an oily suspension. In this suspension, N-0923 is essentially present as a solid phase suspended in the liquid vehicle.

In this patent application, the term "substantially" means more than 90%.

Preferred pharmaceutical compositions are those in which N-0923 is present in the solid phase in an amount of greater than 95%, particularly preferably greater than 97% or greater than 99%.

In the present patent application, the term "oily suspension" means a dispersion in which the continuous phase ("excipient") is present in the form of liquid lipids.

In the present patent application, the term "solid phase" means that N-0923 is present in solid form. In this case N-0923 can be present in free solid form, e.g.as crystalline or amorphous particles, or can also be bound to suitable carriers, e.g.PLGA-microparticles.

A preferred subject of the present invention is to provide a pharmaceutical preparation in which N-0923 is substantially insoluble. After administration of the preparation to living organisms, for example in the form of a subcutaneous depot, a sustained (protahierten) release of N-0923 from the solid phase results.

By "substantially insoluble in the pharmaceutical formulation" is meant that less than 10% of the therapeutically active substance used is present in dissolved form in the pharmaceutical formulation at room temperature.

Particularly preferred formulations are those in which less than 5%, particularly preferably less than 3% or very particularly preferably less than 1% of N-0923 is dissolved.

Thus, a preferred subject of the present invention is an anhydrous pharmaceutical composition containing N-0923.

In the present application, the term "anhydrous" means a water content of less than 3%.

Particularly preferred formulations have a water content of less than 1%, or more preferably less than 0.5%.

After administration, the active substance can be released from the solid phase over a longer period of time, whereby a therapeutically effective plasma content of 0.1 to 15ng/ml is achieved over at least 24 hours, preferably over 36 hours, particularly preferably over 48 hours, despite the rapid biological elimination of N-0923. The plasma content preferably used is 0.2 to 10ng Rotigotine/ml, particularly preferably 0.3 to 5ng/ml, very particularly preferably 0.4 to 3 ng/ml.

Advantageously, the frequency of administration of N-0923 can thereby be reduced to once a day or once every second or third day.

The subject of the present invention is therefore a pharmaceutical preparation for administration of N-0923 over at least 24 hours, preferably over at least 36 or 48 hours.

N-0923 can be converted into a readily water-soluble, pharmaceutically acceptable salt which is insoluble or only slightly soluble in aliphatic solvents, in particular in oils, and is therefore substantially insoluble in corresponding anhydrous preparations.

Examples of such pharmaceutically acceptable salts are, for example, salts of inorganic or organic acids, such as hydrochlorides, hydrobromides, bisulfates, carboxylates or alkanesulfonates or salts with metal cations.

A particularly preferred example is the hydrochloride of N-0923.

In contrast, the free base of N-0923 is less suitable, it is readily soluble in organic solvents and aliphatic hydrocarbons.

Preferred pharmaceutical compositions are those wherein N-0923 is present as substantially free crystalline or amorphous particles.

Drug depot forms containing crystals of N-0923 are particularly preferred.

N-0923 crystals can be prepared by simple methods by recrystallizing the corresponding salt of N-0923 from an organic solvent, as described in USP-4564628.

The crystalline N-0923 hydrochloride can be prepared, for example, as follows: the N-0923 hydrochloride is first dissolved in methanol under heating, the methanol is distilled off, the residue is dissolved in acetone at above 50 ℃ and then N-0923-HCl is crystallized out over several hours at low temperature. For further purification, it can be recrystallized, for example, from acetone or propanol.

Finally, the crystalline, hydrophilic N-0923 salt is incorporated into an anhydrous injectable formulation in which the salt is poorly soluble or substantially insoluble.

Such pharmaceutical preparations may, for example, be based on a pharmaceutically acceptable continuous phase of a liquid glycerol fatty acid ester, a fatty alcohol, an aliphatic hydrocarbon (e.g. paraffin) or a hydrophobic liquid silicone, and in which the N-0923 salt, for example N-0923 hydrochloride, is introduced in crystalline form. After administration to a patient, the hydrophilic crystalline N-0923 salt will be released only slowly and therefore slowly from this lipid-containing or hydrophobic phase.

Thus, in a preferred embodiment, the present invention relates to an anhydrous, hydrophobic pharmaceutical composition comprising a solid, preferably crystalline salt of Rotigotine, which allows to adjust a continuous plasma level of 0.2-10ng Rotigotine/ml during the total administration period, with an administration interval of at least 24 hours.

The dose of N-0923 administered and the plasma levels obtained therefrom can be controlled, on the one hand, by the concentration of active substance in the preparation and, on the other hand, by the injection volume selected.

The volume can thus be varied within a wide range of 5-1500ml, so that the dosage can be adjusted in a particularly simple manner to the individual condition of the patient.

The preferred volume of administration is 10-500ml or 100-1000 ml.

The concentration range of N-0923 is determined primarily by the pharmacological activity of N-0923 following depot administration. A suitable concentration range of N-0923 is 0.01-10% (w/v), preferably 0.02-5%, particularly preferably 0.1-2%.

A suitable daily dose of Rotigotine is, for example, from 0.5 to 40mg, preferably from 1 to 20mg, particularly preferably from 2 to 15mg, very particularly preferably from 2 to 10 mg.

In one embodiment, the pharmaceutical composition is formed as an oily suspension containing the solid phase N-0923, the continuous phase of which is a lipid.

Pharmaceutically usable lipids are, for example, vegetable oils such as almond oil, olive oil, poppy oil, peanut oil or sesame oil; higher fatty acids such as oleic acid; and mono-, di-, tri-fatty acid esters of mono-or polyhydric alcohols such as isopropanol, 1, 3-propanediol, glycerol, 1, 2-butanediol or 1, 2, 3-butanetriol.

In a preferred embodiment, the pharmaceutical formulation is an oily suspension, the excipients of which consist essentially of polyol-fatty acid-esters.

The term "polyol-fatty acid-ester" in the present application also includes mixtures of various polyol-fatty acid-esters.

As the polyol component of the polyol-fatty acid-ester, polyols having 2 to 4 carbon atoms and a variable number of hydroxyl groups are preferred. Suitable examples are 1, 3-propanediol, glycerol, 1, 2, 3-butanetriol, 1, 2, 4-butanetriol or 1, 3-butanediol.

Particular preference is given to glycerol, 1, 3-propanediol and/or 1, 3-butanediol as polyol component of the continuous phase.

The total degree of esterification of the polyol-fatty acid esters of the continuous phase is preferably from 80 to 100%, particularly preferably from 90 to 100%.

The chain length of the fatty acids in the polyol-fatty acid-esters of the excipient is preferably 6 to 22 carbon atoms, particularly preferably 6 to 14 carbon atoms.

Here, the excipient preferably comprises more than 60% of saturated fatty acids. It is particularly preferred that the excipient comprises more than 90% saturated fatty acids.

As a main component of the excipient, medium chain triglycerides (MKT) are particularly preferred, which mainly comprise saturated fatty acids with a chain length of 8-10 carbon atoms and are described in the pharmacopoeia.

A preferred subject of the present invention is therefore the N-0923 drug depot form, which is formed as an oily suspension and contains excipients consisting essentially of MKT.

MKT is typically a substance that has proven effective for use in systemic administration forms. MKT is advantageously biodegradable, non-irritating, and has excellent physicochemical properties for use in injectable drug forms. MKT is therefore particularly suitable as an excipient for the pharmaceutical compositions of the invention.

There may be mentioned the commercially available triglyceride-caprylic/capric acid-ester, commercially available under the trade name Miglyol812^R(condea corporation).

The content of continuous phase (excipient) in the pharmaceutical composition is derived from the concentration of active substance, humectant and possible remaining adjuvants and is generally greater than 75%, preferably 88-99.8%; very particularly suitable concentrations are 94-99%.

In a preferred embodiment of the invention, the pharmaceutical composition is an oily suspension further comprising a humectant. The term "wetting agent" here means a substance which lowers the interfacial tension between the surface of the excipient and the surface of the active substance.

Humectants are known to those skilled in the art. The following wetting agents are mentioned here as examples of non-limiting protective ranges:

condensation products of polyhydric alcohols and carboxylic acids, such as isopropanol, glycerol, 1, 3-butanediol, 1, 2, 4-butanetriol, 1, 2, 3-butanetriol, 1, 3-propanediol, sucrose, sorbitan, propylene glycol, polyoxyethylene sorbitol or fatty acid esters of dextrin.

Condensation products of polyhydric alcohols and long-chain alcohols, such as polyoxyethylene cetyl alcohol or polyoxypropylene cetyl alcohol.

Preferred wetting agents for use in the pharmaceutical compositions of the present invention consist essentially of polyol-fatty acid-esters.

In a preferred embodiment, the pharmaceutical composition according to the invention essentially contains a polyol-fatty acid-ester with a monoester content of more than 60%, preferably more than 90%, as wetting agent.

The polyol-fatty acid ester preferably contains a polyol having 2 to 6 carbon atoms, such as glycerin, 1, 3-butanediol, 1, 3-propanediol, 1, 2, 3-butanetriol, 1, 2, 4-butanetriol, isopropanol, sucrose or sorbitan.

For the pharmaceutical compositions of the invention, particular preference is given to using polyhydric alcohol-fatty acid esters containing glycerol or 1, 2, 3-butanetriol as wetting agent.

The preferred chain length of the fatty acids in the polyol-fatty acid-esters of the wetting agents is from 6 to 22 carbon atoms, particularly preferably from 6 to 14 carbon atoms.

The polyol-fatty acid monoester of the wetting agent here comprises preferably more than 60% of saturated fatty acids. It is particularly preferred that the polyol-fatty acid-monoesters contain more than 90% saturated fatty acids.

In a more preferred embodiment of the invention, glycerol or 1, 2, 3-butanetriol esterified with saturated fatty acids having from 6 to 14 carbon atoms is predominantly used as wetting agent.

It is particularly preferred to use as wetting agent a commercially available product described in the pharmacopoeia, such as glyceryl monocaprylate (Imwitor308, Condea).

More particularly preferred are glycerol-containing monolauratesAs a pharmaceutical composition of a humectant, the ester may be sold, for example, under the trade name Imwitor312^RAnd (6) purchasing. Glyceryl monolaurate is a typical substance permitted as a food additive in germany and is particularly suitable for use in the depot form of the invention.

A particularly preferred subject matter of the present invention is therefore a pharmaceutical composition comprising a solid phase N-0923, a liquid phase excipient and a humectant, wherein the humectant consists essentially of glycerol monolaurate and/or glycerol monocaprylate.

In a more preferred embodiment, the Rotigotine-containing anhydrous pharmaceutical composition is phospholipid-free. The inventors have surprisingly found that the addition of lecithin, described in the literature as a wetting agent, counteracts the inhibitory effect of the crystalline Rotigotine-containing formulation.

Accordingly, one aspect of the present invention is to provide an anhydrous pharmaceutical inhibiting form comprising a crystalline salt of Rotigotine and no lecithin.

The concentration of the humectant is determined by the amount of active material. The humectant concentration must be sufficient to ensure wetting of the active material particles. This can be determined in a simple manner by suitable tests for the person skilled in the art. On the other hand, care must be taken that the wetting agent is chosen to be used in a concentration such that the wetting agent does not crystallize out.

Suitable concentration ranges (w/w) for the wetting agent are 0.02 to 10%, preferably 0.1 to 5%, particularly preferably 0.5 to 2.5%, in which case the concentration of the wetting agent is always adapted to the concentration of the active substance.

The pharmaceutical compositions of the present invention may also contain adjuvants and additives known to those skilled in the art of pharmacy. It is thus suitable that the additive is a lipid-soluble antioxidant such as vitamin E, when the composition contains, for example, excipients and/or humectants which contain unsaturated fatty acids. In addition, the pharmaceutical composition may contain a thickening agent as needed.

In another aspect of the invention, the pharmaceutical composition of the invention comprises the following components:

(a) the amount of N-0923 in the solid phase,

(b) an excipient consisting essentially of a polyol-fatty acid-ester having a total degree of esterification of greater than 80%,

(c) a wetting agent consisting essentially of a polyol-fatty acid-ester having a monoester content of greater than 60%.

Suitable excipients and wetting agents for this purpose have been illustrated and discussed above.

Another aspect of the invention is the preparation of N-0923 depot forms.

Such depot forms can be prepared in a particularly simple and advantageous manner, in which solid N-0923 is suspended in a liquid oil phase. The vehicle for the oil phase is a polyol-fatty acid-ester, preferably a triester of a polyol having 2-4 carbon atoms and a fatty acid having a chain length of 6-14 carbon atoms, such as a medium chain triglyceride. Furthermore, as wetting agents, it is possible to add polyhydric alcohol monofatty acid esters, preferably monoesters of polyhydric alcohols having 2 to 6 carbon atoms with fatty acids having a chain length of 6 to 14 carbon atoms, for example glycerol monolaurate. In a preferred embodiment of the preparation process, crystalline N-0923, preferably crystalline hydrochloride salt, is used and the composition can be prepared without the addition of water.

Suitable concentrations (w/w) for use in the preparation of the depot form of N-0923 according to the invention are: n-0923 is 0.01 to 10%, preferably 0.02 to 5%, particularly preferably 0.1 to 2%; the excipient is 75-99.9%, preferably 88-99.8%, particularly preferably 94-99%; and the wetting agent is 0.02 to 10%, preferably 0.1 to 5%, and particularly preferably 0.5 to 2.5%.

It is another aspect of the present invention to provide a substantially anhydrous pharmaceutical composition comprising N-0923, preferably in crystalline form.

The pharmaceutical compositions of the invention are suitable for use substantially on mucous membranes such as nasal mucosa or for parenteral application.

The composition is particularly suitable for administration by injection, either via conventional needle injectors or via a needleless injection system. Such needleless injection systems are described, for example, in US 5840062 and US 4913699. The injection may be carried out by methods known in the art for administration in depot form, such as subcutaneous, intradermal, intramuscular or intracranial, e.g. intraventricular injection.

Subcutaneous, intradermal or intramuscular administration is preferred, and subcutaneous administration is particularly preferred.

It was unexpected to achieve plasma levels of N-0923 that produced therapeutic correlations over 48 hours with the formulation of the present invention formed very simply. The bioavailability of N-0923 of the pharmaceutical composition of the invention is greater than 70% and the plasma active substance content achieved is substantially linear with the in vivo dose administered (see figure 4).

Therefore, the therapeutic composition of the present invention is excellent for chronic treatment of diseases caused by disturbance of dopamine-metabolism. Examples of such diseases are parkinson's disease or restless leg syndrome.

The formulations of the invention herein may be used in monotherapy, or in combination with other anti-Parkinson's disease agents.

The term "anti-parkinson agent" here means an active substance which is suitable for having a favorable effect on a pathologically altered dopamine metabolism and/or for otherwise therapeutically or prophylactically reducing or preventing the development of parkinson's disease or for maintaining and/or alleviating the concomitant symptoms associated with parkinson's disease.

Examples of such anti-parkinson agents are known to those skilled in the art. The following group is representative of non-limiting examples of suitable additional active substances: metabolic dopamine precursors, dopamine receptor agonists, dopamine transport blockers, MAO-blockers, muscarines, receptor antagonists, glutamate-receptor antagonists, catechol-O-methyl transferase blockers, neurotrophins (neurotrophins), Immunophilin (Immunophilin) -ligands, histamine-antagonists, antioxidants, glutathione converting enzyme-activators, anti-Apoptose-actives, or calcium antagonists.

Suitable representatives are, in particular, levodopa, methyldopa, biperiden, pargylin, rasagiline, selegiline, lisuride, pergolide, bromocriptine, cabergoline, benztropine, ropinirole, amantadine, memantine, 1-cyclohexyl-1-phenyl-3- (3-piperidinyl) propanol, diphenhydramine, dihydroergocryptine, tolcapone, entacapone, methathixene, propiconazole, budipine, ponalprenol, pramipexole, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).

The active substance may be administered together with N-0923 in the pharmaceutical formulation of the present invention or may be presented as a separate injectable or non-injectable formulation, such as a "kit-of-parts". The additional antiparkinson-active substances here can also be formulated with a delay or with no delay.

By the present invention there is provided for the first time an injectable depot formulation which is capable of releasing a therapeutically effective amount of the formulation over a period of at least 24 hours. Thus, another aspect of the present invention is the use of N-0923 for the preparation of depot drugs.

The pharmaceutical compositions of the invention described in this patent application are also suitable for the administration of the N-0923 derivative, which is described in US 4564628. Thus, another subject of the invention is the drug depot form of the N-0923 derivative and the use of the N-0923 derivative in the preparation of a depot drug.

Another aspect of the present invention is the use of solid phase N-0923 in the preparation of a heat sterilizable medicament. It has been unexpectedly shown that N-0923 remains stable during the heating of the sterilization process, as long as it is present in a solid phase. In contrast, dissolved N-0923 suffers significant thermal decomposition during autoclaving (Autoklavieress) (see example 4).

A preferred subject matter of the present invention is the use of crystalline N-0923, in particular its hydrochloride salt, for the preparation of heat-sterilizable medicaments.

The term "heat sterilizable drug" means in the present patent application that the decomposition of the active substance is less than 1% over 20 minutes when the drug formulation is heated at 121 ℃ under 0.2 mPa.

Another subject of the invention is the preparation of sterile pharmaceutical compositions containing N-0923 by autoclaving pharmaceutical preparations containing the solid phase N-0923. An example of autoclaving of the pharmaceutical preparation according to the invention is a treatment at 121 ℃ and 0.2mPa for 20 minutes.

In a preferred embodiment, N-0923 forms a crystalline hydrochloride salt, which is present in an oily suspension.

Another aspect of the invention is a kit for the preparation of a medicament for the treatment of parkinson's disease or leg tremor, the kit comprising a pharmaceutical composition of the invention and an injection device.

The injection device may relate to an injection system which is still to be infused with the pharmaceutical composition or which has been filled with the pharmaceutical composition of the invention. The injection system may be equipped with a conventional needle or a needle-free injection system may also be used.

Another subject of the invention is a kit comprising a plurality of doses of the pharmaceutical composition of the invention and a plurality of injection devices, for example weekly doses or monthly doses.

Another aspect of the invention provides a kit comprising a pharmaceutical composition of the invention and N-0923 or another anti-Parkinson's disease agent in an oral or transdermal administration form.

For example, a combination of injectable and oral administration forms in a kit may be advantageous to prevent or eliminate the excessive drop in plasma levels when one reservoir is depleted and before a new reservoir is applied.

A preferred embodiment is therefore a kit formed from an injectable depot form of N-0923 and an oral formulation of a rapid influx anti-parkinson agent.

An example of a fast-flowing oral dosage form is described in EP-651997.

Furthermore, a preferred subject of the invention is a kit comprising a pharmaceutical preparation of N-0923 according to the invention and a transdermal delivery form of administration of N-0923.

The following examples serve to illustrate the invention:

example (b):

preparation and crystallization of N-0923

Preparation of crystalline N-0923 and crystallization was carried out as described in USP-4,564,628. Crystalline N-0923 can also be prepared separately, in which N-0923 hydrochloride is first dissolved in methanol under heating, the methanol is distilled off, the residue is dissolved in acetone at temperatures above 50 ℃ and N-0923-HCl is then crystallized out at low temperatures over a period of several hours. For further purification, recrystallization can be carried out in, for example, acetone or propanol.

2. Preparation of N-0923 suspension containing 1% N-0923 and 0.1% GML

(a) Preparation of the continuous phase

1411.2g of Miglyol812 were weighed in a Duran bottle. 14.4g of Imwitor312 was added to Miglyol, followed by heating to 80 ℃ for 30 minutes with stirring. The clear solution was cooled to room temperature and filtered.

(b) Preparation of suspensions

1188g of the solution prepared in (b) was transferred to a glass laboratory reactor, 12g of N-0923 was added and homogenized with Ultraturrax under nitrogen at 10,000 rpm for 10 minutes. The suspension was filled into brown glass bottles under operating Ultraturrax (2,000 rpm).

3. N-0923 containing 0.5, 1.5 and 2% N-0923 and 0.5%, 1% or 1.5% GML Preparation of suspensions

The preparation was carried out as described in 1, but the corresponding weighing was varied.

Heat sterilization of N-0923

A0.6% aqueous solution of N-0923 hydrochloride (batch I) was heat-treated with a 1% suspension of N-0923 from corresponding example 2 (batch II) at 120 ℃ and 0.2Pa for 20 minutes. In addition, a 0.5% aqueous solution of N-0923 was heat-treated under nitrogen atmosphere under pressure (formulation III).

The amount of decomposition was then determined photometrically.

Upon aqueous hydraulic thermal treatment of formulations I and III, 1.5% of each of N-0923 was shown to thermally decompose into decomposition products. In contrast, in formulation II, less than 0.5% decomposition was indicated.

5. Release of N-0923 from the depot of the invention in rats

Sprague-Dawley rats were subjected to subcutaneous Bolus-injection of an oily N-0923 crystal suspension of the following composition:

n-0923: 0.5 or 1%

Imwitor312： 1％

Miglyo 1812: adding to 100 percent

Every 48 hours the following doses were administered:

1mg/kg (0.2ml/kg of 0.5% suspension)

3mg/kg (0.5% suspension 0.6 ml/kg)

10mg/kg (1% suspension of 1 ml/kg)

30mg/kg (3ml/kg of 1% suspension)

Plasma samples were taken at 6, 24 and 48 hours after the 2 nd and 46 th dose and analyzed for N-0923 concentration by LC-MS-MS. The values were averaged from the values of 6 animals. The results are shown in FIG. 1.

6. Release of N-0923 from the depot of the invention in rats

The experimental arrangement was as in example 5, except that the dose administered was 12.5mgN-0923/kg body weight per 48 hours.

Measurements were taken and quantified at 2, 4, 8, 24, 32 and 48 hours after the 22 nd dose. The plasma levels of the individual animals are shown in figure 2.

7. Release of N-0923 from inventive depot in monkeys

Subcutaneous Bolus-injections of oily N-0923 crystal suspensions of the following composition were performed daily to Cynomolgus monkeys:

n-0923: 0.5 or 1%

Imwitor312： 1％

Miglyo 1812: adding to 100 percent

The administration was carried out at doses of 0.25, 1 and 4mg/kg per day. Plasma samples were taken at 2, 6 and 24 hours after the 3 rd and 85 th dose and analyzed by LC-MS-MS

The measurements for each animal are given in figure 3. Figure 4 shows the relationship between the dose used and the maximum plasma concentration produced.

Claims (23)

1. A pharmaceutical composition in the form of a depot containing the active substance N-0923.

2. Pharmaceutical composition according to claim 1, characterized in that it is an oily suspension in which the active substance N-0923 is present in the form of a salt and in a substantially solid phase.

3. Pharmaceutical composition according to one of the preceding claims, characterized in that it is anhydrous.

4. The pharmaceutical composition according to any of the preceding claims, wherein N-0923 is present in crystalline form.

5. The pharmaceutical composition according to any of the preceding claims, wherein N-0923 is present as a crystalline hydrochloride salt.

6. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is an oily suspension, the continuous phase of which consists essentially of the polyol-fatty acid-ester.

7. The pharmaceutical composition of claims 2-6, wherein the continuous phase consists essentially of polyol-fatty acid-esters comprising 1, 3-propanediol, glycerol, 1, 2, 3-butanetriol, 1, 2, 4-butanetriol, or 1, 3-butanediol as the polyol component.

8. The pharmaceutical composition of claims 2-7, wherein the continuous phase consists essentially of polyol-fatty acid-esters comprising fatty acids having a chain length of 6-22 carbon atoms.

9. The pharmaceutical composition of claims 2-8, wherein the continuous phase consists essentially of medium chain triglycerides.

10. The pharmaceutical composition of claims 2-9, further characterized in that the pharmaceutical composition further comprises a humectant.

11. The pharmaceutical composition of claim 10 wherein the humectant consists essentially of a polyol-fatty acid-ester having a monoester content of greater than 60%.

12. The pharmaceutical composition of claims 10-11, wherein the humectant consists essentially of a polyol-fatty acid-ester containing 1, 3-propanediol, glycerin, 1, 2, 4-butanetriol, 1, 2, 3-butanetriol, 1, 3-butanetriol, or sorbitan as the polyol component.

13. The pharmaceutical composition of claims 10-12, wherein the humectant consists essentially of a polyol-fatty acid-monoester comprising a fatty acid having a chain length of 6-14 carbon atoms.

14. The pharmaceutical composition of claims 10-13, wherein the humectant consists essentially of glycerol monolaurate and/or glycerol monocaprylate.

15. An anhydrous pharmaceutical composition comprising a crystalline N-0923 salt in a hydrophobic liquid phase and having a continuous plasma concentration of 0.2-10ng N-0923/ml over a period of at least 24 hours after administration to a patient.

16. Pharmaceutical composition according to one of the preceding claims, for subcutaneous or intramuscular administration.

17. Pharmaceutical composition according to one of the preceding claims for the treatment of disorders associated with disturbances of dopamine metabolism.

18. Pharmaceutical composition according to one of the preceding claims, further characterized in that it contains at least one other active substance against parkinson's disease.

Use of N-0923 or a derivative of N-0923 for the preparation of a deposit-medicament.

20. Use of solid phase N-0923 for the preparation of a heat sterilizable medicament.

21. Use according to claims 19-20, characterized in that N-0923 is present as crystals.

22. Preparation of a sterile pharmaceutical composition containing N-0923, characterized in that it comprises autoclaving a pharmaceutical composition containing the solid phase N-0923.

23. A kit for treating parkinson's disease or tremor leg disorders, comprising:

(a) a pharmaceutical composition according to any one of the preceding claims.

(b) An injection device.