DE4140195A1 - Stable nano-sol of sparingly water soluble pharmaceutical - has external phase of gelatin selected to balance charge on drug particle to improve bioavailability - Google Patents

Abstract

Prepn. of colloidally dispersed system of a pharmaceutical (I) sparingly soluble in water comprises (a) selecting a gelatin (deriv.) or collagen hydrolysate having an isoelectric point (IEP) such that at a particular pH it will neutralise the charge on particles of (I), (b) converting the selected cpd. to aq. soln. form, (c) adjusting the pH (in accordance with (IEP) such that nanoparticles of (I) formed will be stabilised by (almost) complete charge neutralisation, and (d) before or after step (c), (I) is dissolved in the aq sol or a soln. of (I) is combined with the aq. sol. (I) can be replaced by other sparingly soluble organic and/or inorganic cpds. (Ia). Also new are the nanosols themselves. They consist of (a) an inner phase of (I) or (Ia) of particle size 10-800 nm., having a negative or positive surface charge, (b) an external phase of gelatin (deriv.) or collagen hydrolysate with opposite charge and the charge balance between the 2 phases is almost isoionic. USE/ADVANTAGE - The systems are useful in tablets (with rapid or slow release), capsules, parenteral or bioadhesive formulations. The bioavailability of almost any (I) can be improved (by increasing the dissolution rate/without use of harmful additives, and the total (I) dose may be reduced. The process is simple, can use many different sorts of gelatin and by balancing the charges, Ostwald ripening (growth of the larger colloidal particles) is prevented, resulting in a stable, monodisperse system

Description

The present invention relates to a method for manufacturing position of a colloid-disperse system of in water poorly soluble drugs according to claim 1 or of inorganic and / or orga, poorly soluble in water African compounds according to claim 23. It further relates towards a pharmaceutically administrable nanosol, d. H. a stable colloid-disperse system of poorly soluble in water Chen drugs with gelatin according to claim 37. Furthermore it concerns a nanosol, i. H. a stable colloid disper system of inorganic sparingly soluble in water and / or organic compounds or mixtures of organi compounds with gelatin according to claim 52.

The Difficulty of Drugs with Problematic Biover Availability in a satisfactory pharmaceutical application It is well known to bring the form into a clear form. 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 an 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  

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: solvent volume,
c _s : saturation solubility of the substance concerned 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 to increase 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 who are 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, a total of drug release will deteriorate rather than improved. Apart from that, side effects are due to 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-48 26 689) describes a method of manufacture Position of colloidally distributed particles of water insoluble Chen organic compounds. There are extensive tests try to find 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-consuming 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-A-02 75 796) describes the preparation of a also finely divided system with drugs, the however, a defined polymer is required as a carrier. Polymer and drug are dissolved in a solvent and precipitates with a non-solvent. Subsequent steps to separate the Nanoparticles, e.g. B. by filtration or centrifugation be performed. In the manufacture is also a Stabilizer additive (surfactants or similar carriers) necessary, to minimize particle 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 at the beginning (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.

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 claims 1 and 23 and by the nanosol according to claims 37 and 52 ge solves.

The invention thus also relates to the nanosol Claim 52 for use in the manufacture of a pharmaceutical medicinal preparation with improved bioavailability, which contains this nanosol as active component, as well as the relevant pharmaceutical preparations according to claim 46 to 51.  

The invention furthermore relates to pharmaceutical additives preparations for use in the treatment of the sick units z. B. cardiovascular diseases, rheumatism or gout, Diabetes, etc. when using a drug, e.g. B. nifedipine, Indomethacin, glibenclamide, etc. in the form of nanoparticles in a stable colloid-disperse system with gelatin hold.

Gelatin is a scleroprotein obtained from collagen-containing material, which has different properties depending on the manufacturing process. It essentially consists of four molecular weight fractions which influence the physicochemical properties as a function of the molecular weight and the percentage by 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 are usually between 10 and 40 weight percent. Molecular weights below the α-gelatin are referred to as 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 acid 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 tine type B). Through the special ones given below Manufacturing processes can also achieve other IEP's will. Common to all types of gelatin is her amphoteric behavior in an aqueous environment. At pH values that the macromolecule is not identical to the IEP always loaded before.  

Colloidal dispersions are generally 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 ge shows up in the solution called task 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 organic compound, especially one Stabilize drug in the form of a nanosol.

In the context of the invention it has now been shown that the ge charged, colloidal drug particles then stabilized when there is a charge balance between these particles and an oppositely charged gelatin, one Collagen hydrolyzate or a gelatin derivative is reached. This state is the isoionic point (IIP). It shows it is surprising that the Ostwald ripening of the colloidal drug particles according to the invention is prevented. The particles are almost monodisperse and are prevented from growing. The overall system is then referred to as the nanosol according to the invention.

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 colloidal 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 Stabilization of an inorganic, colloidal dispersion 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 so one Particle aggregation are prevented. In contrast, was about Stabilization mechanism, e.g. B. for drugs, so far nothing known.

Further patent applications of ALFATEC-Pharma GmbH, given also the PAZ drug development company mbH, from the same day concern the acute form of 2-aryl propionic acid derivatives (11 AL2704), the slow release form of Dihydropyridine derivatives (11 AL2705), the acute form of S and R-ibuprofen (11 AL2706), the slow release form of S- and R- Ibuprofen (11 AL2707), the acute form of S- and R-Flurbi profen (11 AL2708), the slow release form of S and R flurbiprofen (11 AL2709), the acute form of glibenclamide (11 AL2710) and the acute or sustained release form of indolylacetic acid derivatives (11th AL2711 or 11 AL2712). Your revelation also becomes Subject of the disclosure of the present patent application made.

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, usual 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 of 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 in the 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 Types of gelatin that 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 that forms into oral dosage forms such as B. hard gelatin capsules, granules / pellets or Tablets can be processed.

If 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 drug forms "(11 AL2713) by the same applicant be described by the same day, whose revelation too  on the subject of the disclosure of the present Patent application is made.

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, in particular 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 drugs are also enan tiomerically pure active ingredients 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 been astonishingly 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 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 sustained 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. These 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 removed by desalination Ion exchange resins are removed (see generally for Gelatin: 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 washing several times, 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 of extraction.  

After the process step of extraction, 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 gelatin soluble in cold water can be obtained by targeted degradation with collagenases.

Example II Process for obtaining 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 when using 0.005 to 0.1 N 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 minutes.

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

Example III Procedure for achieving an IEP from 3.5 to 6

Starting material containing collagen, preferably gap or Ossein, becomes a temporary ashtray after the wash subject. There are two process variants in the Liquor ratio 1: 1.3, which is either a saturated Lime milk suspension or a 0.1 to 1 N 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 sometimes, at concentrations of 1 N sodium depending on the degree of shredding, leach the material Is open minded for 6-12 hours. 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 weight 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 is also different. In the case of gelatin derivatives, the state of charge can also depend on the type of codification.

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. As 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 cargo have the precipitated particles. Hence, 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 it can be time consuming and inaccurate zeta potential measurement entirely will.

In many cases it will be enough for this Quick 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 a pH of 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 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. I.e. 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 u. 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 used Water in sol form;
• b) the pH of the solution found in the preliminary tests is set;
• c) one or more water-miscible, organic Solvent, 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 shell 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 produced 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 under (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.

Above is a pharmaceutically applicable nanosol and a method for its production with various Embodiments described. However, the invention relates more generally a nanosol, i. H. a stable, highly disperse System of inorganic and / or poorly soluble in water organic compounds with gelatin that marked is through

• a) an inner phase from the inorganic and / or organic compound (s) that is a particle has a size of 10 to 800 nm and a has a negative or positive surface charge (be to sit),
• b) an outer phase of gelatin, collagen hydrolyzate or a gelatin derivative, which (s) positive or negative is loaded
• c) an approximately or completely isoionic Charge state of the inner and outer phase.

Such a nanosol can be used as a liquid, aqueous nanodisper sion. But it can also be used as a solid, resuspendier bare nanodispersion. A is particularly preferred Nanosol, in which the inorganic and / or organic Ver  bond or organic compounds a particle sizes distribution below 300 nm, in particular 10 to 100 nm points (have). With positively charged particles of the orga niche connection (s), the gelatin has a negative net charge, while with negatively charged particles the organic compound (s) have a positive net charge sits.

The process for producing such a nanosol from in Water-poorly soluble inorganic and / or organic Connections is carried out according to the procedure that above in connection with the manufacture of pharmaceutically administrable nanosols has been described.

The following examples are intended to illustrate the invention:

example 1

Drug:
Ibuprofen (Racemate), active acid

Gelatin type:
commercially available, type B, 170 Bloom

Nanosol production:
Analog procedure I
Gelatin / drug weight ratio:
1.5: 1

The working pH range for Ibutropfen 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 a negative Carry surface charge.  

Gelatine 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 Z formed Nanosol has one for pharmaceutical Use a suitable maximum stability.

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

250 ml of 96% ethanol are added.

10 g 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 pharmaceutical form are processed.

Particle size measurements with a BI-FOQELS on-line particle Sizer results in 65% particle sizes of 450 nm.

Example 2

The procedure is as in Example 1, but one is used Gelatin, which according to Example III (gelatin production) 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 pre-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 stability optimum.

500 g of a 7.5% aqueous gelatin solution from above specified type of gelatin 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 for the production of Nanosol 5% converted into sol form with water.

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 carried out as in Example 1, but for one of the carried out a pH of 4.0.

The optimum stability 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 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% smaller particle sizes 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 performed by 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 Minutes (75 rpm / 900 ml 0.1 N 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 (58)

1. A method for producing a colloidally disperse Sy stems 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 (its) 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) the gelatin, the collagen hydrolyzate or the gelatin derivative is converted into the aqueous sol form,
• c) the pH value as a function of the IEP of the gelatin is adjusted to such a value that the nanoparticles of the drug which are formed are stabilized almost or completely charge-neutral, and
• d) before or after stage c) the drug dissolves in the aqueous gelatin sol or a solution of the drug is combined with the aqueous gelatin sol.

2. The method according to claim 1, characterized in that in step d) 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 in that one

• e1) the drug precipitates in the form of nanoparticles.

4. The method according to claim 1 or 2, characterized in that one

• e2) the colloid-disperse solution obtained in stage d) is spray-dried or freeze-dried and thus obtains a stable resuspendable nanosol that after re-dissolution in an aqueous medium gives a colloid-disperse system in nanosol form.

5. The method according to claims 1 to 4, characterized records that in step d) the drug in one dissolved in water-miscible organic solvents, adds. 6. The method according to any one of claims 1 to 5, characterized ge indicates that the drug is an acid or base is transferred to its salt. 7. The method according to any one of claims 1 to 5, characterized ge indicates that the water-miscible organi the solvent in stage b) the aqueous gelatin sol clogs and in stage d) the drug in solid form this Mi closes and thus solves. 8. The method according to claim 5 or 7, characterized in net that you then the organic solvent removed again.   9. The method according to any one of claims 1 to 3 and / or 8 characterized in that the nanoparticle solution then dries. 10. The method according to claim 9, characterized in that the solution is spray-dried. 11. The method according to claim 9, characterized in that the solution is freeze-dried. 12. The method according to claim 2 or 3, characterized in net that before adjusting the pH to isoionic point in stage c) so the pH represents that the drug forms a salt. 13. The method according to any one of claims 1 to 12, characterized characterized in that one after step d) with Water-miscible organic solvent for the curl tion of the hydration shell of the gelatin molecules is added. 14. The method according to any one of claims 1 to 12, 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. 15. The method according to claim 13, characterized in that to add alcohol. 16. The method according to claim 2, characterized in that one continuously with a colloidal particle adjustable particle size. 17. The method according to claim 16, characterized in that the particle size is measured continuously.   18. The method according to any one of claims 1 to 17, characterized characterized in that it is carried out continuously. 19. The method according to any one of claims 1 to 18, characterized characterized in that a gelatin is used in which largely maintains the native state of collagen is. 20. The method according to claim 19, characterized in that gelatin with a short setting time (peptidan partially <20%). 21. The method according to any one of claims 1 to 20, characterized characterized in that a type A gelatin puts. 22. The method according to any one of claims 1 to 20, characterized characterized in that a type B gelatin is used puts. 23. Process for the preparation of a colloidally disperse system of sparingly water-soluble inorganic and / or organic compounds, characterized in that one

• a) selects a gelatin, a collagen hydrolyzate or a gelatin derivative according to its (its) isoelectric point (IEP) so that its (its) IEP is matched to the state of charge of the particles of the inorganic and / or organic compound such that the gelatin, the collagen hydrolyzate or the gelatin derivative at a certain pH with the undissolved organic compound leads to charge neutrality,
• b) the gelatin, the collagen hydrolyzate or the gelatin derivative is converted into the aqueous sol form,
• c) the pH value depending on the IEP of the gelatin is set to such a value that the forming nanoparticles of the inorganic and / or organic compound are stabilized almost or completely charge neutral, and
• d) before or after stage c) the inorganic and / or organic compound is dissolved in the aqueous gelatin sol or a solution of the inorganic and / or compound is combined with the aqueous gelatin sol.

24. The method according to claim 23, characterized in that in step d) the dissolved inorganic and / or orga African compound before merging with the aqueous Gelatinesol briefly in colloidally disperse form of Na transferred noparticles and the dispersion thus obtained of nanoparticles continuously with the aqueous Gelatin sol combined. 25. The method according to claim 23 or 24, characterized in that

• e1) the inorganic and / or organic compound fails in the form of nanoparticles.

26. The method according to claim 23 or 24, characterized in that

• e2) the colloid-disperse solution obtained in stage d) is spray-dried or freeze-dried and thus obtains a stable resuspendable nanosol which, after redissolution in an aqueous medium, gives a colloid-disperse system in nanosol form.

27. The method according to claim 23 to 25, characterized in net that you then the organic solvent removed again. 28. The method according to any one of claims 23 to 25 and / or 27, characterized in that the nanoparticle The solution then dries. 29. The method according to claim 28, characterized in that the solution is spray-dried. 30. The method according to claim 28, characterized in that the solution is freeze-dried. 31. The method according to claim 24, characterized in that before adjusting the pH to the isoionic Point in step c) adjusts the pH so that the or ganic compound forms a salt. 32. The method according to any one of claims 23 to 31, characterized characterized in that one after step d) with Water-miscible organic solvent for the curl tion of the hydration shell of the gelatin molecules is added. 33. The method according to claim 32, characterized in that to add alcohol. 34. The method according to claim 24, characterized in that one continuously with a colloidal particle adjustable particle size. 35. The method according to claim 34, characterized in that the particle size is measured continuously. 36. The method according to any one of claims 23 to 35, characterized characterized in that it is carried out continuously.   37. Pharmaceutically administrable nanosol, ie stable colloid-disperse system of water-poorly soluble drugs with gelatin 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.

38. Nanosol according to claim 37, characterized in that it is in the form of a liquid, aqueous nanodispersion. 39. Nanosol according to claim 37, characterized in that it is present as a solid, resuspendable nanodispersion. 40. Nanosol according to one of claims 37 to 39, thereby ge indicates that the drug has a particle size distribution below 400 nm. 41. Nanosol according to claim 40, characterized in that the drug has an average particle size from 10 to 800 nm, in particular from 10 to 400 nm points. 42. Nanosol according to one of claims 37 to 41, 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.   43. Nanosol according to one of claims 37 to 42, thereby ge indicates that the drug has a solubility in Water at room temperature of less than 5 g / l, esp has particularly less than 1 g / l. 44. Nanosol according to one of claims 37 to 43, characterized ge indicates that with negatively charged drug par the gelatin has a positive charge below the egg has a pH of 9.5 in aqueous solution. 45. Nanosol according to claim 37 to 43, characterized net that with positively charged drug particles the gelatin has a negative charge above a pH 3.5 in aqueous solution. 46. Nanosol according to claim 37, characterized in that the pharmaceutically administrable form is a tablet which releases the drug quickly. 47. Nanosol according to claim 37, characterized in that the pharmaceutically administrable form is a tablet that slowly releases the drug. 48. Nanosol according to claim 37, characterized in that the pharmaceutically applicable form a solid, pul deformed nano filled in hard gelatin capsules represents dispersion. 49. Nanosol according to claim 37, characterized in that the pharmaceutically administrable form is a semi-solid Represents dosage form. 50. Nanosol according to claim 37, characterized in that the pharmaceutically administrable form is parenteral Represents dosage form.   51. Nanosol according to claim 37, characterized in that the pharmaceutically applicable form is a bioadhesive Represents dosage form. 52. Nanosol, ie stable, highly disperse system of poorly water-soluble inorganic and / or organic compounds or mixtures of inorganic compounds with gelatin, characterized by

• a) an inner phase from the organic compound (s) 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.

53. Nanosol according to claim 52, characterized in that it is in the form of a liquid, aqueous nanodispersion. 54. Nanosol according to claim 52, characterized in that it exists as a solid resuspendable nanodispersion. 55. Nanosol according to one of claims 52 to 54, characterized ge indicates that the inorganic (s) and / or organic compound (s) a particle size distribution below 300 nm, in particular 10-100 nm (exhibit).   56. Nanosol according to one of claims 52 to 55, characterized is characterized by an external phase that is additional Contains polyvinylpyrrolidone such as 5: 1 to 500: 1. 57. Nanosol according to one of claims 52 to 56, thereby ge indicates that with positively charged particles the Gelatin has a negative charge above a pH of 3.5 in aqueous solution. 58. Nanosol according to one of claims 52 to 56, thereby ge indicates that with negatively charged particles the Gelatin a positive charge below a pH 9.5 in aqueous solution.