United States Patent:  6,066,332

Assignee:  Alfatec-Pharma GmbH (Heidelberg, DE); PAZ Arzneimittelentwicklungsgesellschaft mbH (Frankfurt am Main, DE)

Filed:  December 1, 1995

A medicament for immediately treating painful, inflammatory and/or febrile diseases contains as active substance ibuprofen as a racemate, as a racemic mixture with its enantiomers, as a pseudoracemate (mixtures of equal parts of S- and R-ibuprofen) or as a mixture of different parts of S- and R-ibuprofen in a range between pure S- and pure R-ibuprofen in the form of a pharmaceutically applicable nanosol and satisfies all requirements of an immediate-effect pharmaceutic form. It can in addition be combined with a slow-release medicament that contains as active substance ibuprofen as a racemic compound, as a pseudoracemate (mixtures of equal parts of S- and R-ibuprofen) or as a mixture of different parts of S- and R-ibuprofen in a range between pure S- and pure R-ibuprofen, in the form of a pharmaceutically applicable, gelatine-based nanosol.

Abstract of Description of the Invention

The present invention is based on the object of developing a medicament and a process for its preparation for the rapid release and influx of ibuprofen, which largely avoid the disadvantages mentioned above for the prior art.

This object is achieved according to the invention by means of an immediate-effect medicament. This object is furthermore achieved by the use of a pharmaceutically administrable nanosol of ibuprofen.

Preferred embodiments of the invention are mentioned and claimed in the dependent claims. In the context of the present invention, completely novel combinations of immediate-effect and sustained-release forms are moreover possible. Customary individual doses for the ibuprofen racemate are 200 mg to 800 mg and in the case of S-ibuprofen 50 mg to 400 mg are customary. In the context of the present invention, ibuprofen is present either as the racemate, as a racemic mixture with its enantiomers, as the pseudoracemate (mixture of equal amounts of S- and R-ibuprofen) or in a mixture of different proportions of S- and R-ibuprofen in the range between pure S- and pure R-ibuprofen.

In the International (PCT) Patent Application of the present date having the title "Pharmazeutisch applizierbares Nanosol und Verfahren zu seiner Herstellung" (Pharmaceutically administrable nanosol and process for its preparation) of ALFATECH-Pharma GmbH corresponding to the German Patent P 41 40 195.6 of May 12, 1991, whose contents are also made the contents of the present patent application, nanosols and processes for their preparation are described which make it possible to stabilize colloidally disperse solutions of poorly water-soluble active substances by gelatin, collagen hydrolyzates or gelatin derivatives if the isoionic point (=charge equilibrium) between gelatin and the surface-charged active compound particles is at least approximately established. In this process, the system active compound particle/gelatin is brought to charge equilibrium by compensating the surface charge of the particles by a corresponding opposite charge of the gelatin molecules. This is achieved by establishment of a specific charge on the gelatin molecules which depends on their isoelectric point and the pH of the solution.

According to the invention the fact is therefore utilized that gelatins, collagen hydrolyzates or gelatin derivatives (nearly independently of the viscosity) lead to a stable colloidally disperse system in nanosol form when the isoionic state of charge is present between pharmaceutical substance particles and gelatin, collagen hydrolyzate or gelatin derivative.

On the other hand, gelatins according to the prior art were only employed for the stabilization of an inorganic, colloidally disperse system. Thus German Pharmacopeia 9 describes a colloidal injection solution of radioactive gold which is prepared with gelatin. It was merely proposed here that the macromolecule be present as a "cementing substance" between the individual colloid particles and thus particle aggregation be prevented. However, nothing was known until now about the stabilization mechanism, e.g. for pharmaceutical substances.

The International (PCT) Patent Applications of the present date of ALFATEC-Pharma GmbH and PAZ Arzneimittelentwicklungsgesellschaft mbH corresponding to said German Patent Application (of May 12, 1991) relate to the immediate-effect form of S- and R-ibuprofen (P 41 40 179.4), the sustained-release form of S- and R-ibuprofen (P 41 40 172.7), the immediate-effect form of S- and R-ibuprofen (P 41 40 184.0) and the sustained-release form of S- and R-ibuprofen (P 41 40 183.2). Their disclosure is also made the subject of the present patent application.

The advantages of this novel product are thus obvious. As a result of controlled absorption of the active compound even in the stomach, the rate of influx and bioavailability of ibuprofen which was previously to be classified as problematical on account of its poor solubility, can surprisingly be significantly improved.

In order to explain the physiological background of the absorption of pharmaceutical substances in general and the improved absorption rate of the nanosols according to the invention adequately, first a consideration of the mechanism of physiological absorption of pharmaceutical substances as is also presented in relevant publications is necessary. However, the present invention is neither tied to the following attempt at a scientific explanation of the phenomena occurring according to the invention nor can it be restricted by this.

Passive pharmaceutical substance absorption takes place according to the present state of knowledge (theory according to Brodie et al.), if the following conditions exist:

a) the gastrointestinal membrane acts as a lipid barrier,

b) the pharmaceutical substance is only absorbed in dissolved and uncharged, i.e. nonionized form,

c) acidic pharmaceutical substances are preferably absorbed in the stomach and basic pharmaceutical substances preferably in the intestine.

After the oral uptake of a pharmaceutical substance into the body, its absorption, i.e. the crossing into the general circulation (biophase) is prevented to a great degree by physical barriers, namely

by the mucus layer and an aqueous layer adhering thereto

the cell membranes of the intestinal epithelial cells with the glycocalyx covalently bonded thereto and

the so-called "tight junctions" which connect the epithelial cells with one another on their apical side.

These barriers presuppose that absorption of pharmaceutical substances takes place through the lipid double layers fundamentally independently of their distribution mechanism and state of charge (so-called passive diffusion).

The epithelial cells of the entire gastrointestinal tract are covered with a mucus layer which consists of mucins (glycoproteins), electrolytes, proteins and nucleic acids. In particular, the glycoproteins form with the main components of mucus, namely water, a viscous gel structure which primarily performs protective functions for the underlying epithelial layer. The mucus layer is bound to the apical surface of the epithelial cells via the glycocalyx. The glycocalyx likewise has a glycoprotein structure which is covalently bonded to components of the membrane double layer of the epithelial cells. The branched polysaccharides of the glycocalyx, which are either directly covalently bonded to amphiphilic molecules of the double membrane or to the proteins incorporated in the double membrane, possess charged N-acetylneuraminic acid and sulfate radicals and are therefore negatively charged, which can lead to an electrostatic bond or repulsion of charged pharmaceutical substance molecules or of electrostatically charged particles respectively. The epithelial cell membranes consist of phospholipid double layers in which proteins are anchored via their hydrophobic regions. The phospholipid double layers with their lipophilic content represent a further barrier for the transport of the pharmaceutical substances to be absorbed.

From this description, it clearly follows that charged pharmaceutical substance molecules or electrostatically charged particles therefore only have a very low chance of being absorbed via the oral administration route.

The nanosols according to the invention for the first time provide the technical teaching to form a system with which these abovementioned obstacles to absorption can be overcome. As the active compound nanoparticles are stabilized in neutrally charged form by the gelatin according to the invention, they can be transported through the negatively charged glycocalyx without relatively great obstructions, in contrast to other described nanoparticles of the prior art, which are not or cannot be stabilized in neutrally charged form. According to the invention, the adjustment of the isoionic state of charge can additionally be effected in coordination with the physiological conditions.

As the active compound nanosols according to the invention can pass through the glycocalyx without obstacle, without being bonded or repelled by electrostatic effects, they thus also reach the surface of the epithelial cells and are available there in a high concentration.

Active, carrier-mediated transport mechanisms or phagocytosis can now also make a significant contribution to the absorption of the active compound nanosols.

The nanosols employed according to the invention are distinguished by high stabilities, in particular in the acidic range, without flocculating or crystallizing out. This means that the nanosol is available to the gastric mucosa for absorption for a sufficiently long period during the gastric residence period and independent of pH variations which occur, e.g. due to the effect of food.

At pHs below 2, the stability of the nanosol can be further improved by selection of a type of gelatin suited to this pH range.

The particles of the nanosols, after their preparation, after resuspension of the dried powder and after resuspension from a pharmaceutical form, are present in particle sizes from 10 to 800 nm, preferably below 400 nm, and moreover in nearly monodisperse form. In the resuspended state, the nanosol is furthermore well dispersed in the stomach as a nanodispersion, which creates optimum conditions for absorption. As the nanoparticles are present in stabilized form, they can surprisingly be absorbed as such without them previously having to be dissolved. A solution equilibrium in advance as with micronized powders or water-soluble salts is thus unnecessary in any case. They therefore behave, looked at biopharmaceutically, as a true solution, but without being one of these.

For the first time, controlled absorption in the gastrointestinal tract is possible even during the gastric residence time as a result of the present invention. The absorption is no longer restricted to the small intestine region and a rapid influx of ibuprofen is facilitated.

It is thus surprisingly possible to achieve for the first time with a tablet prepared according to the invention, in comparison with the prior art, a t_max value of less than 2 h, in particular less than 1 h.

Additionally, an increase in the blood level maximum value c_max can also be detected. The increase in c_max can therefore in certain circumstances result in a dose reduction with the same activity. In addition to the rapid onset of action, the rapid influx leads to an earlier elimination from the plasma so that the systemic loading compared with conventional medicaments is advantageously reduced. As a result, the duration of action itself is not reduced in practice, because at the site of action, in particular in inflammatory processes, a substantially longer residence period of the active compound can be expected. The half-lives in the plasma in the case of ibuprofen are about 2 h. In the synovial fluid, on the other hand, half-lives of 10 h to 12 h were found.

As in vitro experiments have shown, the danger of recrystallization in the stomach and thus a delay in absorption (lag time) can be excluded as a result of the mentioned long stabilities of the nanosols according to the invention.

Because of the various mechanisms of action for the S- and the R-enantiomer (S-ibuprofen primarily has peripheral action, while the enantiomeric R-ibuprofen in particular has a central action), mixtures of S- and R-enantiomers containing various proportions of the individual enantiomers may be preferred in the individual case.

Furthermore, the immediate-effect form of ibuprofen can also be combined with a sustained-release formulation of ibuprofen.

As a particular embodiment, a powdered or granulated immediate-effect nanosol can be combined with a matrix tablet, as is described in the International (PCT) Patent Application having the title "Sol-gesteuerte Thermokolloidmatrix auf Gelatinebasis fur perorate Retardformen" (Sol-controlled thermocolloid matrix based on gelatin for oral sustained-release forms) (81 AL 2737) of ALFATEC-Pharma GmbH of the same date, corresponding to German Patent Application P 41 40 192.1 e.g. in a hard gelatin capsule. The contents of said patent application are also made the contents of the present patent application.

Such a pharmaceutical form initially releases the active compound rapidly and the maintenance dose (matrix tablet) constantly with high reproducibility according to a zero order rate law.

The dried nanosol can be processed to give pharmaceutical forms, for example to give a tablet, and resuspended from this. An enteric coating for protection from "inactivation" of the active compound by the acidic gastric pH is thus superfluous.

The danger of an overdose due to taking repeatedly is excluded by the rapid onset of the analgesia as a result of absorption in the stomach. All the disadvantages and dangers of the enteric coating mentioned are inapplicable. The present invention thus also serves to increase patient compliance. This all constitutes a decisive contribution to the medicament safety demanded.

Fundamentally, the product according to the invention can be processed to give all pharmaceutical forms which are to be administered orally, in particular it can be filled into hard gelatin capsules directly as a powder. It is also outstandingly suitable for direct tableting. Processing to give beverage granules, rapidly dissolving pellets or beverage tablets is of particular interest for administration as an immediate-effect form which has a rapid influx.

In principle, the procedures and process variants mentioned in the abovementioned German Patent Application P 41 40 195.6 "Pharmazeutisch applizierbares Nanosol und Verfahren zu seiner Herstellung" (Pharmaceutically administrable nanosol and process for its preparation), which are referred to once more in the following, are suitable for the preparation of the nanosols according to the invention.

Claim 1 of 28 Claims

1. A dosage formulation that provides for the release of nanoparticles which comprises:

(a) an inner phase that comprises at least one nanoparticle comprising ibuprofen having an average size ranging from 10 to 800 nanometers; and

(b) an outer phase that comprises a compound selected from the group consisting of gelatin, collagen hydrolyzates and mixture thereof;

wherein said inner phase is negatively charged and said outer phase is positively charged when the dosage formulation is dissolved in an aqueous solution having a pH of less than 9.5 or said inner phase is positively charged and said outer phase is negatively charged when said dosage formulation is dissolved in an aqueous solution having a pH of higher than 3.5.

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