DE4140195C2 - Pharmaceutical nanosol and process for its manufacture - Google Patents

Description

The present invention relates to a method for manufacturing Provision of a nanosol of poorly water-soluble medicines neistoffen according to claim 1. It continues to apply a pharmaceutically administrable nanosol, d. H. a stabi The colloidal-disperse system of sparingly water-soluble Drugs with gelatin according to claim 18.

The Difficulty of Drugs with Problematic Biover Availability in a satisfactory pharmaceutical application Bringing it in a form is well known. About 30% of all Active substances in medicinal products fall into this group. For it must i. a. a quick release of the active ingredient is out ner preparation after application, d. H. a fast Transfer to the dissolved, resorbable form, gefor be changed in order to achieve acceptable therapeutic success len. Assuming that the absorption process in vivo is not the speed-limiting step all technological processes for drug release improvement on influencing two parameters in the return the so-called Noyes-Whitney equation:

in which

: amount of solids going into solution per time = dissolution rate,
D: diffusion coefficient of the substance molecule in question,
A: effective solid or crystal surface that is accessible to the solvent (wettable surface),
d: thickness of the diffusion layer,
V: volume of solvent,
c _s : saturation solubility of the substance in question and
c _t : concentration of the substance in question at solution at time t

mean. This equation gives a mathematical expression for the rate of dissolution of substances in general (here Drugs). The are for the pharmacist Only the saturation concentration (sat solubility) of the drug as well as the effective surface of the fabric that can be attacked by the solvent. A Enlargement of these two parameters should also be an Er increase the release speed.

Classic methods of increasing the saturation solubility of drugs are e.g. B .:

• a) the addition of water-miscible organic solder resources, or
• b) the use of hydrotropic substances.

However, these measures have the disadvantage that on the one hand the organism with toxicologically questionable substances on the other hand, increased solubility in vivo destroyed by the recrystallization processes the. In addition, the amount to be used is often not sufficient, to dissolve a required dose of drug.

Therefore, in recent times, the solubilization of drugs substances through surface-active, micelle-forming substances or the formation of cyclodextrin inclusion compounds  wrote. However, both applications have the essential Disadvantage that primarily dissolved drug in the organism actually not freely available, but from its complex must be released with the excipient. That is, all in all drug release will deteriorate rather than improved. Apart from that, side effects are limited by borderline surfactants cannot be excluded.

A surface enlargement of drugs is possible through Mi chronization possible. However, this processing is very difficult and expensive and has its limits in a party size of 1 µm. However, the smaller the powder particles are, the more they tend to aerophilicity and the Degree of wetting upon contact with solvents (effective Surface A) becomes low - the dissolving speed becomes rather degraded. Therefore the addition of hy drophilic carriers are necessary.

Other known methods for producing small particles are z. B. the following:

Violanto (US-A-4,826,689) describes a method of manufacturing Position of colloidally distributed particles of water-insoluble Chen organic compounds. There are extensive tests necessary to find the optimal values for the parameters Tem temperature, stirring speed and addition speed of the aqueous precipitation liquid to dissolve the solid Determine compound in organic solvent. Because only if these preconditions are met does education ensure of the particles described. A subsequent separation operation should free the particles from the organic liquid. Stabilization measures may require one quite time and costly zeta potential measurement, according to which is an addition of viscosity-increasing substances or Measured surfactants to the aqueous precipitation liquid, the to prevent particle aggregation.  

Fessi (EP 0 275 796 A1) describes the production of a also finely divided system with drugs that ever but a defined polymer is required as a carrier. Polymer and drug are dissolved in a solvent and precipitates with a nonsolvent. After Steps to separate the nanoparticles, e.g. B. by filtration or centrifugation. A stabilizer additive is also included in the manufacture (Surfactants or similar carriers) necessary to remove the particles to minimize aggregation.

In the above processes there are always complex additives necessary, the use of which is neither specifically predetermined can, still for the reasons mentioned above (toxicological risk) is desirable. Therefore, it is an easy one Production of stable nanosoles with as little as possible Third-party additives crucial for pharmaceutically relevant applications turns.

Pharm. Acta Helvetica 53, No. 1, 1978, pages 17 to 23 and US-PS 41 07 288 relate to gelatin or other macro Molecular existing nanoparticles, which may also be May contain pharmaceutical substances. About the He no appearance of the pharmaceutical substances made concrete statements. The gelatin is in the form of Nanoparticles that are cross-linked with aldehydes. DE 37 42 473 A1 describes the production of colloidal par particles, the gelatin as a viscosity-increasing thickener medium included. Preferably, to influence the Drug loading Acids added as peptizers.

The present invention is therefore based on the object the bioavailability of anorga that is poorly soluble in water African and organic compounds, especially medicines  substances, by increasing their dissolving speed without closing to improve the set of harmful additives. This on is given by the method according to claim 1 and solved by the nanosol according to claim 18.

Gelatin is a scleroprotein obtained from collagen-containing material, which has different properties depending on the manufacturing process. It consists essentially of four molecular weight fractions, which influence the physicochemical properties depending on the molecular weight and percentage weight. The higher z. B. the proportion of microgel (10 ⁷ to 10 ⁸ D), the higher the viscosity of the aqueous solution. Commercial varieties contain up to 15 percent by weight. The fraction of α-gelatin and its oligomers (9.5 x 10 ^{4/10 5} to 10 ⁶ D) are crucial for the gel strength and generally lies between 10 and 40 weight percent. Molecular weights below the α-gelatin are called peptides and can be up to 80 percent by weight in conventional gelatin qualities (low bloom).

Depending on the processing of the raw material (acidic or basic Disclosure) gives gelatins, their isoelectric points are different. For acidic digested gelatins the IEP is between 6.3 and 9.5 (gelatin type A), for ba sectically digested gelatins between 3.5 and 6.5 (gela type B). Through the special ones given below Manufacturing processes can also achieve other IEP's become. Common to all types of gelatin is their amphoteric Behavior in an aqueous environment. At pH values that are not with are identical to the IEP, the macromolecule is always charged in front.  

Colloidal dispersions are generally a. metastable and flake therefore sediment out. By predominating the destabilizing forces caused by van der Waals- Attraction, is the electrostatic repulsion of the at the Surface uniformly charged particles too low, so that larger particles grow at the expense of smaller ones than what Ostwald maturation is called.

Surprisingly, the patent application shows P 41 40 195.6 that the setting of their La condition by protonation or deprotonation relative to the isoelectric point (IEP) completely sufficient is, according to the invention, a sparingly soluble in water Stabilize drug in the form of a nanosol.

The loaded, colloidal drug has been shown to particles are then stabilized when there is a charge balance between these particles and an oppositely charged one Gelatin, a collagen hydrolyzate or a gelatin derivative is reached. This state is the isoionic Point (IIP). It is surprisingly shown that the Ostwald ripening of the colloidal drug particles according to the Invention is prevented. The particles are almost there monodisperse and are prevented from growing. The Ge The entire system is then referred to as the nanosol according to the invention net.

Fig. 1 shows a schematic representation of the adjustable charge states of gelatins as a function of pH and IEP, the IEP may be depending on the make from 3.5 to 9.5. Below pH 3.5 almost all types of gelatin are positively charged. In the basic range above pH 9.5, all types of gelatin are negatively charged.

According to the invention, the fact is therefore exploited that Gelatins, collagen hydrolyzates or gelatin derivatives (almost regardless of the viscosity) then to a stable colloid-disperse system in nanosol form if the isoionic state of charge between drug particles and Gelatin, collagen hydrolyzate or gelatin derivative is present.

In contrast, gelatin according to the prior art was only used for Stabilization of an inorganic, colloid-disperse Systems used. For example, B. the DAB 9 a colloidal solution of injection of radioactive gold using Gelatin is made. You just presented yourself before that the macromolecule as a "cement substance" between the individual colloid particles and thus a particle aggregation is prevented. In contrast, was about the Stabili sation mechanism, e.g. B. for drugs, so far nothing known.

Further patent applications by ALFATEC-Pharma GmbH, given also the PAZ Arzneimittelentwicklungsgesellschaft staft mbH, from the same day concern the acute form of 2-aryl-propionic acid derivatives (DE 41 40 185 A1), the slow release form of dihydropyridine derivatives (DE 41 40 194 A1), the acute form von S- and R-Ibuprofen (DE 41 40 179 A1), the slow release form of S- and R-ibuprofen (DE 41 40 172 A1), the acute form of S- and R-Flurbiprofen (DE 41 40 184 A1), the slow release form of S- and R-Flurbiprofen (DE 41 40 183 A1), the acute form of Glibenclamide and the acute or slow release form of indole vinegar acid derivatives (DE 41 40 178 A1 or DE 41 40 191 A1) where additional aspects can be seen.

The degree of loading of the nanosols according to the invention with medication substance expressed in g of drug per g of gelatin, Collagen hydrolyzate or gelatin derivative is aimed at general according to the dosage for the concerned  Drug. It can be 1: 200 to 1: 0.5 usually 1:50 to 1: 1, in particular 1:20 to 1: 3. This makes the Nanosol astonishingly for such drugs are very suitable, usually high must be dosed, such as. B. Ibuprofen (single dose for analgesic therapy = 200 mg, for rheumatism therapy = 400 mg). An improvement in bioavailability according to the invention here means a dose reduction, the scope of which for a Therapy can be crucial. With less drug thus a more efficient therapy with less toxic Possible strain on the organism.

The drug particles in the nanosol according to the invention preferably an average particle size of 10 to 800 nm, especially below 400 nm.

The drug for the nanosols according to the invention has been prefers a solubility in water at room temperature of less than 5 g / l, in particular less than 1 g / l.

If necessary, common pharmaceutical auxiliaries substances and / or other macromolecules taking into account the Stability of the product according to the invention in liquid or dried state can be added.

An addition of e.g. B. polyvinyl pyrrolidone has Technologically proven to be particularly suitable. Doing so especially with low molecular weight PVP (e.g. PVP K 15) The stability of the nanosol was not reduced. The Quantity ratio gelatin to polyvinylpyrrolidone can for example in the range from 5: 1 to 500: 1.

Nanosols can be used for the usual types of application nen. For example, the nanosols according to the invention are Use of cold water soluble / modified gelatin suitable for use as parenterals. Modified  Gelatin can e.g. B. be a commercially available plasma expander. Furthermore, the nanosols can be used for pulmonary application or for transdermal application (e.g. semi-solid Drug form) can be used. They are particularly suitable however for sublingual and peroral application and for dosage forms with bioadhesive properties.

Another advantage of the present invention results from the wide range of usable variations Gelatin varieties, which are advantageously simplified technological applications. So you can go through Use of rapidly dissolving types of gelatin Acute forms of tablet-based nanosol arrive consist almost entirely of an auxiliary (e.g. Direct tableting). In addition, one can Nanosol produced according to the invention even when used of high molecular quality gelatine without problems spray or freeze dry.

Spray-dried nanosols result in an easy to dose or granulable powder, which forms oral dosage forms such as B. hard gelatin capsules, granules / pellets or Tablets can be processed.

Are the nanosoles according to the invention (with or without conventional Scaffolders) lyophilized, can be particularly quickly develop releasing drug forms, whereby gelatins with high peptide content are preferred.

Let for the development of oral prolonged-release drug forms Retard nanosoles are advantageous, as in for example in the patent application entitled "Sol- Controlled gelatin based thermocolloid matrix for oral prolonged-release pharmaceutical forms "(DE 41 41 40 192.1) by the same applicant  be described from the same day, from the supplementary Aspects are evident.

Details of special dosage forms that are difficult soluble active ingredients in acute and / or slow release nanosol form may contain from the applications already mentioned be removed.

Also suitable for the nanosols according to the invention Drugs with problematic bioavailability, especially others,

• 1. from the group of strong analgesics, e.g. B. morphine, Dextropropoxyphene, pentazocin, pethidine, buprenorphine;
• 2. from the group of anti-inflammatory drugs / anti-inflammatory drugs (NSAID), e.g. B. indomethacin, diclofenac, naproxen, Ketoprofen;
• 3. from the group of β-sympathicolytica, z. B. Proprano lol, alprenolol, atenolol, bupranolol;
• 4. from the group of steroid hormones, e.g. B. betamethasone, Dexamethasone, methylprednisolone, fludrocortisone and Esters, ethinyl estradiol, medroxyprogesterone acetate;
• 5. from the group of tranquillizers, e.g. B. oxazepam, Diazepam;
• 6. from the group of α-sympatholytics, e.g. B. Dihydroergotamine;
• 7. from the group of hypnotics, e.g. B. secbutabarbital, Secobarbital, pentobarbital;  
• 8. from the group of tricyclic antidepressants, for. B. Nortriptyline, clomipramine, amitriptyline;
• 9. from the group of neuroleptics, e.g. B. chlorine prostheses, Chlorpromazine, haloperidol, trifluopromazine;
• 10. from the group of gout agents, e.g. B. Benzbromaron, Allopurinol;
• 11. from the group of anti-Parkinson drugs, for. B. Levodopa;
• 12. from the group of coronary therapeutic agents or calciuman tagonists z. B. nifedipine u. a. Dihydropyridinderi vate, Gallopamil;
• 13. from the group of antihypertensive drugs, e.g. B. clonidine, Methyl dopa, dihydralazine, diazoxide;
• 14. from the group of diuretics, e.g. B. Mefrusid, Hydrochlorothiazide, furosemide, triamterene, Spironolactone;
• 15. from the group of oral antidiabetic agents, e.g. B. Tolbut amide, glibenclamide;
• 17. digitalis glycosides;
• 18. antiarrhythmics;
• 19. Antibiotics / chemotherapy drugs;
• 20. anti-epileptics;
• 21. anticoagulant;
• 22. antispasmodics;  
• 23. antifungals;
• 24. hormones;
• 25. venous therapeutic agents;
• 26. Immunosuppressants;
• 27. tuberculostatic drugs;
• 28. antivirals;
• 29. cytostatics;
• 30. Provitamins and Vitamins;
• 31. Phytopharmaceuticals
• 32. from the group of drugs for the treatment of acquired immune deficiency (AIDS).

In the sense of the above list of medicinal products are also enan tiomerically pure active substances or pseudoracemates according to the invention suitable.

Furthermore, the nanosols according to the invention can be used for Active ingredients in the field of dietetic foods be used.

It has surprisingly been within the scope of the present Invention showed that a variety of drugs can be converted into nanosol form if, after selecting one suitable gelatin (type A or B with characteristic isolelectric point, molecular weight, etc.) such  Net charge of the molecule is set, which to Charge neutrality (isoionic point = IIP) with the charged drug particles and one for the Drug (acid, base or neutral or amphoteric Substance) selects suitable production according to the invention.

The product obtained according to the invention behaves pharma seen as a real solution, but without the pro to have blemes of the prior art; d. H. on pharma ecologically questionable additives can be dispensed with.

According to the invention, the following advantages are especially ge achieved compared to the state of the art:

• - inorganic and organic which are difficult to dissolve in water Connections are in a form with new properties brought;
• - The procedure is difficult to solve on almost all inorganic and organic compounds applicable;
• - It is simple and without complex devices and apparatus carry out ren;
• - poorly soluble or resorbable in the body Drugs can be converted into a form that behaves like a real solution;
• - This succeeds without chemical change, e.g. B. without the Formation of a derivative, or formation of a chemical Complex;
• - This works without the addition of surfactants or hydrotropic substances;  
• - In this form are difficult to solve compounds in vivo faster and more completely absorbable;
• - the dosage can be reduced;
• - The shape obtained is stable in storage;
• - The biopolymer gelatin or its derivative is a toxicologically safe auxiliary;
• - Gelatin in acute or slow release forms contributes to a good one Compatibility of the drug formulated according to the invention substance at;
• - are the specified manufacturing processes economically.

With a particularly gentle production method you can Preserve types of gelatin that contain only a small percentage of right-handed amino acids and thus similar are constructed like the native collagen molecule. This For example, low-peptide gelatins are notable particularly short solidification times. Such a gelatin is particularly suitable according to the invention. However, it can also commercially available gelatins from the above Composition, heavily degraded gelatins (collagen hydrolyzates or cold water soluble gelatin), modified gelatins and fractionated gelatin (individual fractions or their Mixture) for the production of nanosoles according to the invention be suitable.

A too high proportion of foreign ions (ash content <2%) can have a disruptive effect and should be desalinated with Ion exchange resins are removed (see generally for Gelatine: Ullmann, Encyclopedia of Technical Chemistry, 3. Ed. 1954 vol. 10 and 4. ed. 1976 vol. 12, p. 211; H.E.  Wunderlich: When it comes to gelatin - publisher: German Gelatine Consumer Service, Darmstadt (1972); I. Tomka, gelatin, in: W. Fahrig, U. Hofer, The Capsule, Scientific publishing company mbH Stuttgart, 1983, Pp. 33-57.

Compared to commercially available products, the use of Gelatin, which was produced in a special way, too Nanosoles described in accordance with the invention with increased Stability.

Examples of the production according to the invention particularly ge suitable gelatin grades are given below.

Examples of the production of particularly according to the invention suitable types of gelatin with isoelectric points of 3.5 to 9.5 Example I Process to achieve an IEP from 7.5 to 9.5

Collagen-containing starting material such as B. pork rinds are mixed with an aqueous solution of a 0.45 N mineral acid, preferably sulfuric acid, in a liquor ratio of 1: 1 to 12 Treated for 20 hours. Then the excess acid removed by repeated washing, whereby to shorten the Process sodium bicarbonate can be used. The extraction of the ripe material is done with hot Water at 55-80 ° C at a pH of 2.5 to 4.5. At pH An IEP of 8.5 to 9.5 can be used for values below 3.5 are sufficient, at pH values above 3.5 the IEP is included 7 to 8.5. In this way, different IEP's from 7 to 9.5 depending on the pH value during the extraction.  

After the extraction step, the aqueous Lö solution neutralized and processed as usual.

Through this procedure one can continue to be dependent from the chosen temperature during the Gelati extraction Types with high to medium molecular weight distribution gene received.

At temperatures of 50-55 ° C you get particularly high vis petite and high-blooming qualities. Gelatin varieties with low according to molecular weight or cold water soluble gelatins can be obtained through targeted degradation with collagenases.

Example II Process to achieve an IEP from 4 to 7.5

The collagen-containing starting material is first washed to remove foreign substances, crushed and then finally made homogeneous alkaline by adding magnesite, sodium hydroxide solution or calcium hydroxide by thorough mixing in a liquor ratio of 1: 1.2. The material pretreated in this way is briefly digested under pressure hydrolysis at 1.01 · 10 ⁵ to 2.02 · 10 ⁵ Pa and a pH of the aqueous solution of 8-14. After digestion, the mixture is neutralized immediately and the still hot aqueous gelatin solution is filtered, desalted, concentrated and dried as usual.

If you take a weakly basic disintegrant like Magne sit, you get an IEP of 6 to 7.5 if you work at 1.01 · 10 ⁵ Pa. IEP's of 5 to 6 can be obtained by using a dilute lime milk suspension and using 0.005 to 0.1 mol / l sodium hydroxide solution, IEP's from 4 to 5 can be achieved.

Types of gelatin with a low degree of racemization and low peptide content can be achieved at pressure ratios of 1.01 · 10 ⁵ Pa and residence times of a maximum of 10 min.

Medium to low molecular weight to cold water soluble Varieties result from a correspondingly longer dwell time ten.

Example III Process to achieve an IEP from 3.5 to 6

Starting material containing collagen, preferably gap or Ossein, becomes a temporary ashtray after the entrance wash subject. Here there are two process variants in Liquor ratio 1: 1.3, which is either a saturated Lime milk suspension or a 0.1 to 1 mol / l sodium hydroxide solution Bring effort.

When using a lime milk suspension, the raw mate rial with constant movement for a maximum of 3 to 4 weeks closed. Then the material is added by acid neutralized and washed several times. The further work tion follows as usual. In this way, IEP’s from Set 4 to 6.

When using caustic soda, the ash process can still be performed shorten times, at concentrations of 1 mol / l sodium depending on the degree of shredding, leach the material 6-12 h is open. The neutralization takes place with equimolar amounts of mineral acid and the neutral salts by washing several times or by desalting the in the extraction of aqueous gelatin solution removed. In this process variant, IEP's from 3.5 to 5 received.  

Particularly low-peptide types of gelatin are obtained in the ashtray with a short residence time. In this way, types of gelatin with a high to medium molecular weight distribution (M = 10 ⁴ -10 ⁷ D) can be obtained.

Low-molecular to cold water-soluble types of gelatin can obtained by thermal degradation or enzymatically.

As already mentioned at the beginning and as can be seen from FIG. 1, the absolute, maximum possible net charge of a single gelatin molecule depends mainly on the number of free COOH and NH ₂ groups and the pH of the solution. Since types A, B, collagen hydrolyzates or gelatin derivatives differ in the number of free COOH groups, their maximum possible net charge also differs. In the case of gelatin derivatives, the state of charge can also depend on the type of modification.

Chooses when performing the method according to the invention the suitable gelatin and the suitable one are pre-tested pH value.

First, the physico-chemical properties adjusted working pH range of the drug. When physico-chemical property of the drug are given to consider everything: The solubility (in organic Solvents or water), its property as an acid, Base or neutral substance and its stability against acid and alkalis.

A first quick test determines which load have the precipitated particles. From this follows, un considering the working pH range, choosing one suitable type of gelatin. Are the particles for example negatively charged, you choose a gelatin that is among the  given pH conditions is positively charged. This Quick test to determine the particle charge has the intent share that he without much equipment and time can be carried out. So can be a time consuming and inaccurate zeta potential measurement entirely become.

In many cases it will be enough for this Rapid test with two commercially available gelatins type A and B. an IEP of 9.5 or 3.5 with peptide levels <30% and a bloom number of 200 that continues as standard gelatins be referred to at a pH of 6 in the sol form to convert (5% aqueous solution) and the drug in a water-miscible solvent, such as. B. Ethanol, isopropanol or acetone, to solve and each with to mix the gelatin solutions homogeneously. At the same Dosage of the drug will change in your Charge state unsuitable gelatin a colloidal System either fail to train or become unstable immediately or flocculate the drug. Are the emerging Particles negatively charged, they are more likely to be gelatin solution with type A, which is positively charged at pH 6, stabilized as from the solution with gelatin type B; in the On the contrary, in this case type B either no col train loidal system or the system immediately destabilize. The flocculation of the particles can be done e.g. B. track via a simple turbidity measurement.

In this quick test, the working pH range must be observed in any case. Other gelatins can also be selected as the standard, but they must be selected in their IEP so that they carry opposite net charge at this pH (see also FIG. 1). In most cases, said standard gelatins type A and B will suffice for this rapid test.

Based on the result of the preliminary test, gradual variation of the IEP's through use corresponding types of gelatin and the pH of the solution in smaller areas (e.g. 0.1 pH steps) the optimal ones Conditions for the formation of the nanosoles determined. That means it must the stability optimum, which is by the isoionic point (IIP) is found to be a sufficient stability for the pharmaceutical mentioned To ensure applications.

It may well be the case that one in the sense of the inven acceptable stability of the nanosols already in one narrower pH range (approx. 0.5 units) around the isoionic Point is found, making an adjustment of that point itself is not absolutely necessary. On the other hand, you can also several gelatins for the same, stable results to lead. So for example (example 5) with the oral Anti-diabetic glibenclamide with a type B gelatin an IEP of 5.5 the stability optimum at a pH value of 3.2, while for a type B gelatin with a IEP of 3.8 the stability optimum at a pH of 2.2 lies.

Characterized by a stability maximum of the isoionic point was reached in both cases (the dependence of the net charge of the pH value and the IEP need not be linear, as it is given by the _pK a of the COOH or NH ₃ groups ⁺- ).

According to the invention, other macromolecular substances can also be used in addition to gelatin, collagen hydrolyzates, fractionated Small amounts of gelatin or gelatin derivatives (maximum 5% by weight) can be added. It can be amphoteric or charged substances, such as albumins, Casein, glycoproteins or other natural or act synthetic polypeptides. In special cases  can also anionic polymers such. B. alginates, rubber arabic, pectins, polyacrylic acids and. a. be suitable.

According to the invention, there are several production processes of the nanosoles. It is a exemplary, incomplete list. The specialist can based on his specialist knowledge, other variants elaborate within the scope of the present invention:

Procedure I

This can be used if the drug is a mixture of:
a water-miscible organic solvent and water, or
from several water-miscible organic solvents and water is soluble:

• a) a gelatin selected in the preliminary tests is included Water in sol form;
• b) the pH of the solution found in the preliminary tests is set;
• c) one or more water-miscible, organic Solvents, preferably ethanol, or isopropanol Methanol, is / are added to this solution;
• d) the drug is added to the solution in solid form ben and solved;
• e) the organic solvent (s) is / are ent remotely, preferably by evaporation in vacuo; there the nanosol is created;  
• f) the colloidally disperse solution is then preferred by spray or freeze drying, dried.

The organic solvent has the task of Dissolve drug and also changes the hydration envelope of the Gelatin molecules Procedure II

This embodiment can be used when the doctor Neistoff is an acid or a base, the salt of which is in water is soluble:

• a) a gelatin selected in the preliminary tests is converted into the sol form with H ₂ O;
• b) such a pH value is set, which is the salt formation of the drug enables;
• c) the drug is salted in the gelatin sol solved;
• d) by adding alcohol or similar organic solvent The hydration shell of the gelatin molecules can act as a solvent be relaxed;
• e) by adding a suitable amount of acid or base the pH value is set, which is used to form the isoionic point (IIP) Nanosol;
• f) the colloidally disperse solution is ge as in method I dries.

Stage d) is optional, but preferred.  

Procedure III

This embodiment can be used when the doctor neistoff is a neutral substance:

• a) a gelatin sol is prepared as in (1) a) and b) described.
• b) a second solution from a water miscible or ganic solvent, preferably ethanol, metha nol, isopropanol, acetone and the drug is produced posed.
• c) the two solutions are combined.
• d) the organic solvent is removed and the col Loid-disperse solution is dried.

Procedure IV

• a) As described under (I) a) and b).
• b) In a second solution, a colloid-disperse Sy stem briefly formed with the drug, however without gelatin.
• c) The solution obtained in (b) is continuous with of the gelatin solution.

In step (IV) c) the continuous mixing of the Solutions described under (IV) a) and b) are time-dependent by measuring the particle size on-line with a suitable one Methods such as B. by laser light scattering (BI-FOQELS On-line particle sizer). So that's it  possible, a desired particle size continuously adjust.

All of the methods mentioned are also for collagen hydrolyzates and gelatin derivatives are suitable and can be used in the technical scale are transferred.

The essential steps can be largely automated expire, with processes I to III also continuous are feasible.

The following examples are intended to illustrate the invention:

Example 1

Drug: Ibuprofen (Racemat), active acid
Gelatin type: commercially available, type B, 170 Bloom
Nanosol production: Analog method I
Gelatin / drug weight ratio: 1.5: 1

The working pH range for ibuprofen is preferably un terhalb its _pK a value of 4.6.

The pre-test at pH 4.3 to determine the surface charge the ibuprofen particle results in type B standard gelatin (IEP 3.5 / 200 Bloom) no nanosol. Under same The standard gelatin type A (IEP 9.5 / 200 Bloom) a short-term stable nanosol, in which the present ibuprofen particles have negative surfaces carry charge.  

Gelatin is now used to determine the optimum stability varieties with different IEP's at different pH values tested below pH 4.3. The series of measurements shows that a type B gelatin (IEP 4.9), which at pH 3 a positive net charge, best suited. That after Process I formed nanosol has one for pharmaceutical Use a suitable maximum stability.

500 g of a 3% aqueous gelatin solution above Type are brought to pH 3.

250 ml of 96% ethanol are added.

10 g of ibuprofen are dissolved in this mixture, then that evaporated organic solvents. The so made Nanosol is then spray dried and can be used for appropriate drug form are processed.

Particle size measurements result in 65% particle sizes of 450 nm.

Example 2

The procedure is as in Example 1, but one is used Gelatin that according to Example III (gelatin manufacture) with the same bloom value and the same IEP (4.9).

Particle size measurement results in 70% particle sizes of 265 nm.

Example 3

Drug: dexamethasone, neutral substance
Gelatin type: Type A, 220 Bloom, preparation example I.
Nanosol production: analogous to method III
Gelatin / drug weight ratio: approx. 10: 1

The preliminary test carried out at pH 7 analogously to Example 1 gives in the case of the neutral substance dexamethasone, that a gelatin Type A is suitable.

A type A gelatin (IEP 7.9) with a positive charge stood at pH 5.3 gives the optimum stability.

500 g of a 7.5% aqueous gelatin solution from above specified gelatin type is adjusted to pH by adding acid 5.3 set.

3.5 g of drug are dissolved in 100 ml of acetone.

Both solutions are mixed and the resulting nanosol spray dry after removal of the organic solvent net.

The average particle size of the nanosol is between 260 and 300 nm.

Example 4

The nanosol is produced as in Example 3, but under Use a gelatin of commercial quality with same key figures.

The average particle sizes are in the range of 550 to 630 nm:

Example 5

Drug:
Glibenclamide, active acid

Gelatin type:
Type B, 100 Bloom, preparation example III

Nanosol production:
analogous to method III

Gelatin / drug weight ratio:
100: 1

The working pH range for the weak acid drug Gli benclamid is preferably less than its _pK a value from 6.3 to 6.8.

The pre-test according to the invention and the series of measurements result in a pH of 2.2 for the isoionic state of charge an optimum with a gelatin type B (IEP 3.8).

5 g of gelatin of the above type are now used to produce Nanosol converted to the sol form with water at 5%.

50 mg glibenclamide are dissolved in 30 ml ethanol and 96% homogeneously mixed with the aqueous gelatin solution.

The resulting nanosol is removed after the or ganic solvent lyophilized.

Average particle sizes are 130 nm.

Example 6

Drug:
Propranolol, active ingredient base

Gelatin type:
Type B, 320 Bloom, preparation example II

Nanosol production:
Analog procedure II

Gelatin / drug weight ratio:
4: 1
Working pH range:
9.2

Gelatine selected after the pre-test:
Type B / 320 Bloom, IEP 4.2

In a warm gelatin solution (64 g and 640 ml water) 16 g of propranolol hydrochloride are dissolved at pH 3. A pH of 8.8 is obtained by adding sodium hydroxide solution set, in which a nanosol of propranolol base forms. In this case the isoionic state of charge only roughly reached.

The average particle sizes vary more and are in the range from 650 to 780 nm.

Example 7

Drug:
Indomethacin, active acid

Gelatin type:
Collagen hydrolyzate with a peptide content of 90%, preparation example II

Nanosol production:
Analog procedure II

Gelatin / drug weight ratio:
5: 1

The pre-test is the same as in Example 1, but for one of the carried out a pH of 4.0.

The stability optimum of the nanosol is in the collagen hy drolysate with an IEP of 5.2 and a pH of aqueous drug / gelatin solution of 3.1 reached.

150 g of the collagen hydrolyzate are distilled in 2 l Water dissolved. In this solution, 30 g of indomethacin suspended. The pH value of the system is adjusted with sodium hydroxide solution between 7 and. 8 held. It continues to stir until a completely clear solution is created. After that, through Add a measured amount of hydrochloric acid to the pH 3.1 set, in which the nanosol forms spontaneously.  

The nanosol solution obtained is concentrated and spray dried. The powder obtained becomes an acute form processed further.

Particle size measurement results in 70% particle sizes smaller than 370 nm.

Example 8

Drug:
Niefedipine, neutral substance

Gelatin type:
commercially available, type B, 60 Bloom

Nanosol production:
Analog procedure III

Gelatin / drug weight ratio:
15: 1

The production takes place under light protection (yellow light).

The pre-test is carried out analogously to Example 1, but at a pH of 6.0.

The subsequent series of measurements to determine the Optimum stability results in a type B gelatin (IEP 4.7) a pH of 5.5.

600 g of fully desalinated gelatin specified above and 40 g PVP K 15 are dissolved in 8 l of distilled water at 40 ° C and adjusted to pH 5.5.

40 g of nifedipine are completely dissolved in 1.3 l of ethanol.

Both solutions are mixed homogeneously and the resulting one Spray dried Nanosol after removing the alcohol. The powder obtained is in opaque hard gelatin capsules with a Bottled 10 mg nifedipine per capsule.

The dissolution test (paddle) gives 100% release after 9 min (75 rpm 900 ml 0.1 mol / l HCl).  

Bioavailability is becoming more conventional in vivo Capsule preparation with micronized nifedipine by 25% increased. Maximum blood levels are on average reached after 20 min.

Claims (28)

1. A process for producing a nanosol of poorly water-soluble drugs, characterized in that

• a) selects a gelatin, a collagen hydrolyzate or a gelatin derivative according to its (its) isoelectric point (IEP) so that its (his) IEP is matched to the state of charge of the drug particles so that the gelatin, the collagen hydrolyzate or the gelatin derivative is at one certain pH value with the undissolved drug leads to charge neutrality,
• b) converting the gelatin, the collagen hydrolyzate or the gelatin derivative into the aqueous sol form,
• c) converting the drug in the aqueous gelatin sol into a dissolved form or combining a solution of the drug with the aqueous gelatin sol, and
• d) before or after stage c) the pH value depending on the IEP of the gelatin is adjusted to such a value that the nanoparticles of the drug, which are produced by precipitation, are stabilized almost or completely charge-neutral.

2. The method according to claim 1, characterized in that in step c) the dissolved drug before the verei briefly in col with the aqueous gelatin sol loid-disperse form of nanoparticles and the dispersion of nanoparticles thus obtained continuously Lich combined with the aqueous gelatin sol. 3. The method according to claim 1 or 2, characterized records that in step c) the drug in one dissolved in water-miscible organic solvents adds. 4. The method according to any one of claims 1 to 3, characterized ge indicates that in step c) the drug, the is an acid or base converted to its salt. 5. The method according to any one of claims 1 to 3, characterized in that water-miscible organic solvents in step b) to the aqueous gelatin sol and
in step c) the drug is added in solid form to this mixture and thus dissolves. 6. The method according to claim 3 or 5, characterized in net that you then the organic solvent removed again. 7. The method according to any one of claims 1 to 3 and / or 6, characterized in that the nanoparticle solution then dries. 8. The method according to claim 7, characterized in that the solution is spray-dried. 9. The method according to claim 7, characterized in that the solution is freeze-dried.   10. The method according to claim 2, characterized in that one before adjusting the pH to the new charge central point in stage d) adjusts the pH so that the drug forms a salt. 11. The method according to any one of claims 1 to 10, characterized characterized in that one follows with step c) Water-miscible organic solvent for the curl tion of the hydration shell of the gelatin molecules is added. 12. The method according to any one of claims 1 to 10, characterized characterized in that the gelatin sol Polyvi nylpyrrolidone in a weight ratio of gelatin to polyvinylpyrrolidone such as 5: 1 to 500: 1. 13. The method according to claim 11, characterized in that an alcohol as an organic solvent puts. 14. The method according to any one of claims 1 to 13, characterized characterized in that a gelatin is used in which largely maintains the native state of collagen is. 15. The method according to claim 14, characterized in that gelatin with a short setting time (peptidan partially <20%). 16. The method according to any one of claims 1 to 15, characterized characterized in that a type A gelatin puts. 17. The method according to any one of claims 1 to 15, characterized characterized in that a type B gelatin is used puts.   18. Pharmaceutically administrable nanosol of poorly water-soluble drugs, characterized by

• a) an inner phase from the drug, which has a particle size of 10-800 nm and has a negative or positive surface charge,
• b) an outer phase made of gelatin, a collagen hydrolyzate or a gelatin derivative which is positively or negatively charged,
• c) an approximately or completely isoionic charge state of the inner and outer phase.

19. Nanosol according to claim 18, characterized in that it is present as a liquid, aqueous nanodispersion. 20. Nanosol according to claim 18, characterized in that it exists as a solid, resuspendable nanodispersion. 21. Nanosol according to one of claims 18-20, thereby ge indicates that the drug has an average Liche particle size of 10 to 800 nm, in particular 10-400 nm. 22. Nanosol according to one of claims 18 to 21, characterized is characterized by an external phase that is additional Polyvinylpyrrolidone in a weight ratio of Ge latine to polyvinylpyrrolidone such as 5: 1 to 500: 1 ent holds. 23. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form is a tablet that releases the drug quickly puts.   24. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form is a tablet that slowly releases the drug puts. 25. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form a solid, powdery, abge in hard gelatin capsules filled nanodispersion. 26. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form represents a semi-solid dosage form. 27. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form represents a parenteral dosage form. 28. Nanosol according to one of claims 18-22, characterized ge indicates that the pharmaceutically administrable form represents a bioadhesive dosage form.