CZ420399A3 - Gastroretentive micro-spheres with controlled release and enhanced delivery of active substance - Google Patents

Abstract

A composition for delivering a pharmaceutically active agent with controlled release of the active agent in the stomach environment after a prolonged period of time, the essence of which is that includes a microsphere containing the active ingredient in the interior the microsphere core and i) the water-regulating layer insoluble polymer; and (ii) an external bioadhesive layer a cationic polymer.

Description

Gastroretentive microspheres with controlled release and improved drug delivery

Technical field

The present invention relates to a novel method of retaining pharmaceutical agents in the stomach of a mammal as part of a topical treatment of stomach diseases or to improve the intestinal absorption of active substances having limited absorption capacity in the small intestine of mammals.

The prior art compounds are very much the case

The preferred route of administration of most pharmaceutically active agents is through the gastrointestinal tract. Most pharmaceutically active substances are very well absorbed by the entire intestinal tract, but some usually compounds of polar nature, to a limited extent absorbed in the colon of such compounds, are the major area in which they are absorbed, the small intestine. Some active agents may utilize a natural transport mechanism, such as a receptor-mediated transport mechanism, an active transport mechanism, or other specific transport mechanism, and are known to have so-called small intestine absorption windows.

absorption windows express the fact that the pharmaceutically active substance is absorbed only by the intestinal and non-intestinal regions through the entire small and large intestine. Such a window may be the duodenum, the jejunum, or the ileum, or a portion thereof. Examples

This expression has some limited "fc 4" * (· · · · · · · · · · · · · · · · · · · (I · · · · · · · · · · · · · · · · · 4 of these pharmaceutically active substances (medicaments) are methyldopa and captopril, and it would therefore be advantageous to retain these medicines whose absorption behavior in the small intestine is not ideal for a longer period of time in the stomach above their a major absorption region, for example using a gastroretentive drug preparation.

Such a gastroretentive system would also find utility in the administration of drugs intended to produce a local effect in the stomach. A good example of this type of therapy is the well-known use of antibiotics in the topical treatment of a bacterial infection by Helicobacter pylori (H. pylori). Furthermore, in an article by Hirsche and Pletschette [Campylobacter pylori and Gastroduodenal Ulcers (ed. Rathbone and Heatley), Blaclwell (1989), p. use of other pharmaceutically active substances such as H ₂ -receptor blockers). In addition, the authors of the article report that, if retention of the antimicrobials in the stomach were achieved, drugs with topical efficacy could be administered orally for topical treatment.

Various methods of achieving gastroretence have been proposed in the prior art, including the use of dosage forms that exhibit prolonged gastric retention due to their density or size, or the use of a mechanism based on a putative bioadhesive concept.

The field of gastroretentive dosage forms has been well described by Moes [Crit.Rev.Ther.Drug Carrier Syst., 10, 143 (1993) and Deshpande et al. [Drug Devel. Ind. Pharm., 22,531 (1996)]. The proposed methods described in these publications for extending the residence time of the drug delivery system in the stomach include agents such as fatty acids, pharmacological agents that delay the passage of the active ingredients from the stomach to the small intestine, and means such as developed polymer layers and bubble hydrogels [Park K. and Park H., Proc. Int.Symp.Control.Rel.Bioact.Mater14,41 (1987) and Cargill R., Caldwell IJ, Engle K., Fix JA, Porter PA. and Gardner C.R., Pharm. Res., 5,533 (1988).

Although the concept of using large individual dosage forms to achieve gastric retention at first glance is very attractive, it is known that such use is associated with potential problems in some pancas, including esophageal or small bowel blocking.

Another method of achieving retention of the drug delivery system in the stomach for a longer period of time is to administer a non-disintegrable tablet or capsule having a size greater than about 7 mm and less than about 20 mm along with a large proportion of food. Natural gastric motolite processes ensure that the drug delivery system of this size does not leave the stomach before gastric emptying. The drug delivery system then passes into the intestine under the effect of a physiological process known as the migration myoelectric complex (activito, phase III). However, in many cases where the therapeutic effect of the diet is on the diet, it would be advantageous to administer such active agents to an empty, starved stomach.

In the case of topical treatment of gastric disorders, it would also be desirable to achieve tight adhesion of the drug delivery system to the mucosal surface of the stomach after fluid / food has been emptied from the stomach. Interim attempts to achieve this effect have not yet been successful, nor has any beneficial extension of the stomach residence time in humans been described. Specifying a beneficial extension of residence time in this context means that the stomach residence time in the fasted patients is at least three times longer than the residence time of the control formulation solution.

• ·

* · · · · · · · · · · · · · · · · · · · · · · · · ·

The use of bioadhesive polymers as gastroretentive materials has been well described in the pharmaceutical literature and is also the subject of patent applications [see, for example: Ch ^from ng HS, Park H., Kelly P. and Robinson JR, J.Pharm. Sci., 74, 399 (1985); Longer MA, Ch'ng HS and Robinson JR, J.Pharm. Sci., 74, 406 (1985); and Gurney and Junginger (ed.) Bioadhesion Possibilities of Future Trends, Wissenschaftliche Verlaggesselschaft (1990)].

Tablets and pellets with prolonged gastric retention and bioadhesive properties have been described in International Patent Application WO94 / 00112. Specific uses of micro-adhesive formulations in the treatment of gastric disorders (including bacterial H. pylori infection) have been described in International Patent Application WO92 / 18143. Natural gums, plant extracts and derivatives of acrylic acid or methacrylic acid have been proposed as providing regular drug release and / or prolonged retention of the drug release system in the stomach. The controlled release of furosemide from mucoadhesive (= adhering to the mucosa) microgranules by oral administration of furosemide is described in US Patent 5,571,533. These microgranules are prepared from lipophilic excipients and are coated with mucoadhesive polymers selected from carbomer, polycarbophil, hydroxypropylmethylcellulose, hydroxypropylcellulose or mixtures thereof.

Moes (1993) (see above reference) report that the use of bioadhesive polymers to modify the gastrointestinal transition has been abandoned since such mucoadhesive polymers are unable to regulate or significantly slow the gastrointestinal transition of solid drug delivery systems such as pellets and tablets.

Pellets and other high density single dose units have also been studied in gastroretence [Bechgaard H. and Ladefoged K.J., Pharm. Pharmacol., 30, 690 (1978) and Clarke G.M. Gastrointestinal Transit of Spherical

9

9 9 »····

9

Granules of Differential Size and Density, PhD Thesis (1989), University of London], but this approach has not led to significant progress in humans if the dosage unit density does not exceed 2.0. However, one of ordinary skill in the art knows that such a high density is a significant processing and weight deficiency for a conventional pharmaceutical product.

Low density floating systems in the form of pellets and tablets have also been described [Babu et al., Pharmazie, 45, 268 (1990); Mazer et al., J. Pharmac. Sci. 77, 647 (1988)]. While some progress can be observed with these systems, these systems do not appear to provide an extended residence time of the system in the stomach. However, these systems offer some protection against premature and accidental abandonment of the stomach, although this requires administration of these systems immediately after a meal.

Floating microcapsules having a size of from 0.1 to 2 mm containing sodium bicarbonate and coated with a conventional water-soluble film-forming coating material are described in US Patent 4,106,120. Similar floating granules whose function is based on gas generation have been described in US Patent 4,844,905. Floating capsules have also been described in US Patent 5,198,229. Atyabi et al.

[J.Control.Rel., 42, 105 (1996)] have described bicarbonate-containing ion exchange systems which release carbon dioxide upon contact with stomach hydrochloric acid, which gas is then trapped in a semipermeable membrane surrounding the system bodies, causing the system bodies float. Eugragit RS is mentioned as a suitable coating material. Such particles may allegedly be administered with the diet, but testing of the system under consideration under strictly emptied gastric conditions is not described herein. In addition, no active substance was to be incorporated into said bodies to be sustained release.

9 9 9 9 9 9 9 9

Burton et al. [J.Pharm.Pharmac., 47,901 (1995)] studied gastroretention in humans of ion-exchange resins in the form of negatively charged fine particles as compared to an aqueous solution. Thus, it has been found that the first 60 to 70% of the resin leaves the stomach as quickly as the aqueous solution, but the remaining 30 to 40% of the resin will remain in the stomach for a longer period of time. All test subjects received the resin and aqueous solution after fasting overnight. However, there are neither mentioned nor suggested microspheres containing the active ingredient nor gastroretentive systems having a sustained release ability of the active ingredient.

European patent application EP 635 261 describes coated microparticles with improved active substance absorption consisting of dehydrated microparticles comprising a core of a gelatinizable hydrocolloid on which a cationic polysaccharide film is deposited. The microparticles described herein promote the absorption of the active ingredient in the intestine. Gastroretence is not mentioned here (on the contrary, it is suggested that microparticles may be contained in an enteric coated gelatin capsule to protect the particles until it enters the duodenum). EP 635 261 discloses a pharmacologically useful active ingredient which is incorporated into a matrix of microparticles. Hydrocolides are preferably agar, pectin, xanthan gum, guar gum, carob gum, hyaluronic acid, casein and water-soluble salts of alginic acid. The process for obtaining microspheres is a multistep process in which a solution of a gelling hydrocolloid is added to a medium in which the hydrocolloid is gelled (such as calcium chloride). The microparticles thus formed are separated and suspended in a concentrated active substance solution, from which the active substance diffuses into the microparticles. The microparticles are then separated and suspended in a cationic polysaccharide solution (such as diethylaminodextran).

thereby depositing the polysaccharides on the surface of the microparticles. The coated microparticles are then separated, washed and dried. However, this patent document lacks any indication of how the active ingredient is retained in the particle during said individual process steps. Again, the use of a rate-controlling membrane as part of the microparticle composition is not mentioned. In addition, there is no mention of the preparation of microparticles by spray drying.

Chitosan microspheres and microcapsules have also been described as drug delivery systems. A review has been published by Yao et al. [J.M.S.

Rev.Macromol.Chem.Phy., C35, 155 (1995)]. In preparing such systems, chitosan is crosslinked with a crosslinking agent such as glutaraldehyde. Also known are chitosan microcapsules obtained by a complex coacervation process. Alginate is a suitable negatively charged reagent that can interact with positively charged chitosan [see, for example, Polk et al., J.Pharm. Sci. 83,178 (1994)]. Prolonged drug release and chitosan-based floating granules have been described by Miyazaki et al., Chem. Pharm.Bull., 36, 4033 (1988) and Inouye et al., Drug Des.Deliv., 4,55, 1989. However, the particles described in these documents are large and do not contain a rate-modifying polymer.

Chitosan compositions for the controlled and prolonged release of macromolecules have been described in US Patent 4,895,724. A porous matrix of chitosan in which the macromolecule is dispersed is described. It is reported that chitosan may be cross-linked by various agents including glutaraldehyde, glyoxal, epichlorohydrin and succinic aldehyde. However, the use of microspheres for bioadhesion or gastroretention is not suggested.

Chitosan microspheres have also been described for oral drug delivery [Ohya et al., J. Microencaps., 10,1 (1993); JP 5339149, EP 486,959, EP 392,487]. However, such particles •

They were not prepared to provide a controlled release of the active ingredient.

International Patent Application WO93 / 21906) describes a group of bioadhesive polymers in the form of microcapsules or coatings on microcapsules containing pharmaceutically active substances. Chitosan is described herein as providing poor results in the bioadhesive assay. In addition, the process for preparing chitosan microparticles could have contributed to the negatively charged particles.

In summary, it would be desirable to have a system for releasing the active substance into the stomach, having the following characteristics:

excellent retention time in the starved stomach of mammalian (e.g. human) subjects, high water-soluble and fat-soluble pharmaceutically active substances, and controlled release of such active ingredients over a period of time that is consistent with clinical need and / or improved absorption of active substances by absorption through the small intestine window.

Other desirable properties include:

preparedness of the corresponding formulations using already established pharmaceutical process procedures and applicability in the preparation of such formulations of materials which are approved for use in food or pharmaceuticals or of materials of similar status.

SUMMARY OF THE INVENTION

It has now surprisingly been found that microspheres comprising an inner core (optionally including a gelled hydrocolloid) containing a therapeutic agent (ie, an active agent or drug), a rate-controlling membrane of a water-insoluble polymer (such as ethylcellulose), and an outer ·· 00 • 0

A layer of bioadhesive cationic polymer, which may include a cationic polysaccharide, a cationic protein, and / or a synthetic cationic polymer, can provide the above desirable properties.

According to a first feature of the invention, there is provided an active agent release composition for the controlled release of the active agent in the stomach environment for an extended period of time, comprising a microsphere comprising an active agent in its inner core, and (i) a rate controlling layer of water insoluble polymer; ii) an outer layer of the bioadhesive agent in the form of a cationic polymer (hereinafter referred to as the composition of the invention).

Typically, the compositions of the invention are in the form of a plurality of microspheres which upon administration to a mammal together with a suitable fluid (e.g., water) first float at the stomach level and have a surface that provides desirable interaction between particles and gastric mucous lining or the stomach wall after the liquid / food is emptied from the stomach. The inner cores of the microspheres that contain the drug in the sustained-release drug system are coated with a cationic polymer. The rate-controlling layer may be part of either the inner core of the drug-containing microsphere or the rate-controlling layer may be present as a separate layer. The drug substance may be dispersed uniformly (homogeneously) or non-uniformly (heterogeneously) within the inner core. The compositions of the invention are capable of providing release of the drug substance in the stomach environment [i.e. in the stomach) of the gastrointestinal tract for a prolonged period of time (i.e., a time that is at least twice as long as the time required to drain water from the stomach (under normal conditions)).

Within the scope of the present invention, the term "microspheres" refers to microparticles that are substantially spherical and have a microsphere. * Micron size, and microcapsules (which are microspheres or microcapsules where the drug substance is encapsulated and not homogeneously dispersed in the matrix). Substantially spherical is understood to mean microparticles with good roundness (for example, more than 50% of the particles have a longest measured diameter that is less than or equal to twice the shortest measured diameter, as determined microscopically).

Said microspheres may have a size ranging from 0.5 to 1000 microns, more preferably ranging from 1 to 700 microns, and most preferably ranging from 5 to 500 microns [mean volume diameter (MVD) measured using the laser diffraction method]. It has been found that the above microsphere size range provides good retention in the stomach. Larger particles, such as pellets and granules with a size greater than 1000 microns (e.g., 1000 to 2000 microns) do not have good adhesion.

The compositions of the invention have been found to have low density and initially float at the gastric level after administration with a suitable dosing fluid. When the contents of the stomach are emptied, the particles adhere to the stomach wall and coat it.

Cationic polymers that can be used as bioadhesive agents in the outer layer include synthetic cationic polymers, and in particular cationic polysaccharides and cationic proteins. The material is selected such that the microspheres carry a purely positive charge greater than +0.5 mV, more preferably greater than +5.0 mV and most preferably greater than +10 mV (as measured by microelectrophoresis technique) at pH, 4 in 0.001M buffer (such as is phosphate buffer, McIlvanes buffer or Hepes buffer).

As a cationic bioadhesive material, chitosan in the form of a salt can be advantageously used. Chitosan is non-toxic and is present in the diet. At gastric pH it is a positively charged biopolymer. It is known that chitosan can interact in a «9 •« 99 «9 9 9 • 9 9 9 interaction

999 99 *

9 <9 • 9

Φ »« ··

with negatively charged sialic acid groups in mucin [Fiebrig et al., Progres in Colloid and Polymers Sci., 94, 66 (1994)].

Chitosan is prepared by deacetylation of chitin. The degree of deacetylation of chitosan should be greater than 40%, preferably greater than 60% and most preferably greater than 80%. Chitosan should have a molecular weight of greater than 5,000, preferably greater than 10,000, and most preferably greater than 50,000. Chitosan can be used in the form of a chitosan salt (e.g., glutamate, lactate, chloride or acetate) or a chitosan derivative such as is, for example, N-trimethylchitosan chloride.

Other suitable bioadhesive polymers that may also be used are acidic gelatin (high isoelectric point), polygalactosamine, proteins (polyamino acids) such as polyquaternary compounds, diethylaminoethyldextran polyvinylpyridine, (PTDAE), polyhistidine, polyornithine, polyimine,

DEAE-imine, polylysine, prolamine, (DEAE), polythiodiethylaminomethylethylene DEAE-methacrylate, DEAE-acrylamide, poly-p-aminostyrene, polyoxethane, copolymethacrylates [e.g. Cafquat (see U.S. Patent 3,910,862), polyamidoamines, cationic starches, DEAE-dextran and DEAE-cellulose. The polycationic materials used in the present invention have a molecular weight of more than 5,000, preferably at least 50,000.

Preferred water-soluble polymers for use as the rate-controlling layer are ethylcellulose and polymethyl methacrylate. Water-insoluble polymer refers to a polymer having a solubility in distilled water at pH 7 of less than 1 mg / ml at room temperature. The rate-controlling layer and the cationic polymer may or may not consist of the same material (for example, both may be polymethyl methacrylate).

© A A A A

A A A A A

A AAAA

A AAA AAA

A A A

AAA «A A A A A

When the pharmaceutically active agent used in the composition of the invention is a polar active agent, the inner core of the microsphere may further comprise a gelled hydrocolloid (i.e., a hydrocolloid that gels during the production of the microsphere to provide a uniform structure (crosslinking agent) with the therapeutic agent). hydrocolloids which may be used in the present invention are gelatin, albumin and alginates, for example agar, pectin, xanthan gum, guar gum, locust bean gum, acid, hyaluronic acid, casein, and water-soluble salts of alginic acid. gelled by methods known in the art (for example, by cooling aqueous solutions, by interaction with metal ions, and the like).

As used herein, a polar drug (therapeutic agent, pharmaceutically active agent) is a compound with a partition coefficient between water and octanol at a pH of less than 500.

The compositions of the invention may be obtained by processes that produce compositions having the ability to entrap the drug in the stomach and provide sustained release therein (see above). Thus, the compositions of the invention may be prepared by various techniques such as emulsification followed by solvent evaporation under vacuum, spray coating and the like. However, it has also been found within the scope of the invention that the compositions of the invention can be conveniently prepared by an emulsification process combined with spray drying.

A new two-fold emulsification process (water-in-oil-in-water: w / o / w) can be used to prepare polar drug compositions (which include water-soluble drugs). Surprisingly, it has been found that this specific method can be used to prepare floating microspheres that are positively charged and have the ability to control drug release,

The method is particularly suitable for water-soluble active substances.

The term oil herein refers to a liquid having a water solubility of less than 2 ml (oils) in 10 ml (water) (meaning that such oil is immiscible with water).

By water-soluble active substance is meant herein an active substance having sufficient solubility (e.g. greater than 1 mg / ml, preferably greater than 10 mg / ml) in the external aqueous phase of a double emulsion (wow) to allow formation of microspheres which, after following spray drying, the active ingredient content is sufficiently high (e.g. greater than 10%) to administer the compositions of the invention thus obtained in the form of conventional capsules or a similar oral drug delivery system, such as a sachet which may contain for example, administered by dispersing the sachet content in water and drinking the dispersion obtained.

In preparing compositions of the invention containing polar active ingredients by an emulsification process, the water-insoluble polymer that is used as the rate-controlling layer may be dissolved in the oil phase.

For non-polar pharmaceutically active substances, an oil-in-water emulsification process may be used. In either case, the emulsion may be spray dried. As used herein, non-polar active agents are meant to be pharmaceutically active agents that are sufficiently soluble (ie, greater than 1 mg / ml, preferably greater than 10 mg / ml) in an organic solvent (such solvents include dichloromethane, chloroform, ethyl acetate, and the like) to for the active ingredient to be able to dissolve in the selected organic phase of the oil-in-water emulsion system to a sufficient extent to obtain microspheres having a sufficiently high active ingredient content (e.g. greater than 10%) after subsequent spray drying; to allow the administration of the thus prepared compositions of the invention in a conventional individual

Unit hard capsule (for example of gelatin or starch) or another similar oral delivery system, such as a sachet, the content of which may be administered, for example, by dispersing the sachet content in water and swallowing the obtained dispersion.

In preparing compositions of the invention containing non-polar active agents, the therapeutic agent may be dissolved in the same solvent (i.e., the oil phase) used for the rate-controlling layer.

It will be appreciated by those skilled in the art that the pharmaceutically active agent may be dissolved in, or suspended in, the internal phase used (depending on its solubility in that phase).

In the case of both polar and non-polar pharmaceutically active substances, the bioadhesive cationic polymer is present in the aqueous phase, which is either the aqueous phase of the oil-in-water emulsion or the external aqueous phase of the water-in-oil-in-water emulsion. Said emulsion systems may be prepared by methods well known in the art and described below.

When the compositions of the invention are prepared by the above-described emulsification procedures, suitable concentrations for use in the compositions of the invention are such that the concentration of the gelling hydrocolloid (if used) for preparing the internal phase of the double emulsion is 0.1 to 30. %, preferably 0.5 to 20%. The concentration of the rate-controlling layer in a suitable organic solvent is 0.5 to 20%, preferably 1 to 10%. The organic solvent is preferably dichloromethane. The concentration of the bioadhesive cationic polymer used to prepare the external phase of the double emulsion is 0.05 to 10% by weight, but preferably 0.1 to 5% by weight, and most preferably 0.2 to 2% by weight. The concentration of the pharmaceutically active agent may be 0.01 to 90% depending on the particular active agent used. The above percentages are expressed as • · 9 «, 9 · · 9 9 9« 999 · 9 9 9 9999

9999 9 * 9 9,999,999 · · · 9 9

% By weight of the respective component in the respective phase of the emulsion.

well known chitosan

Once the appropriate emulsion system has been formed, the compositions of the invention can be conveniently prepared by spray drying under conditions that are very well known in the art. For example, the preparation of simple microspheres by spray drying chitosan dissolved in dilute acetic acid has been described in the prior art Sugaya. Kokai Tokyo Koho, JP 6320302). It has now been found that spray drying (spray drying) is a process for the preparation of microparticles containing pharmaceutically active substances which can be easily realized on a large scale.

The emulsion formulation can thus be converted into microspheres using suitable spray drying devices. Suitable spray drying devices are those set forth in the examples which follow. Other suitable useful devices are those commercially available from Buchi (Switzerland), Niro / Aeromatic-Fielder (Switzerland / USA), LabPlant (United Kingdom) and Yamamoto (Japan). The operating conditions of such devices, such as spray solution inlet, spray nozzle size, air inlet and outlet temperature, spray pressure and air flow through the spray dryer, can be adjusted according to the manufacturer's instructions to achieve the desired particle size for the microspheres produced and desired release properties. Such optimal operating conditions can be readily determined by one skilled in the art.

According to a further feature of the invention there is provided a process for the preparation of a composition according to the invention which comprises spray-drying an oil-in-water emulsion or a water-in-oil-in-water emulsion containing the components of the composition according to the invention.

I · · · · · · · ·

Improved gastric retention can be achieved with the compositions of the invention by increasing the pH of the stomach above the normal fasting range (in this case the pH is 1.5 to 2.5). Under these conditions, the sialic acid residues in the mucus are largely in ionized form and are able to interact to a large extent with the cationic polymer. Even some foods cause a pH increase above 5, which lasts for 30 minutes or longer. Patients receiving H ₂ antagonists, proton pump inhibitors or antacids are a special case in which the above is advantageous because of the fact that increasing the pH of the stomach to 4 is due to the effect of the pharmaceutically active agent being administered. Increasing the pH in this manner may be particularly useful in the treatment of a bacterial H. pylori infection.

Thus, in a further aspect of the invention, a kit is provided for use in the treatment of H. pylori infection comprising a H ₂ -antagonizing agent, a proton pump inhibitor or an antacid and a composition of the invention comprising an active agent useful for treating H. pylori infection.

Optionally, the compositions of the invention may be surface cured, for example, if appropriate, by partial cross-linking using glutaraldehyde, formaldehyde, benzydianone, benzoquinone, tripolyphosphate, or other known cross-linking agents to provide an intact bioadhesive coating that would it did not dissolve rapidly in the stomach, which would mean that the desired bioadhesive effect would not be achieved. Cross-linking conditions, such as the required amount of cross-linking agent, are determined by monitoring the zeta microparticle potential and adjusting the operating conditions until the desired zeta potential (as determined, for example, by the low ionic strength (0.001M) microelectrophoresis technique in particles at 0.001M). pH 4.0). Composition · · · · ··· · · ···

0 0 0 · 0 0 0 9 • 9909 0 · 9 9 ··· 900 • · 9 0 9 0

The present invention carries a purely positive charge, which is believed to be the causative agent of the desired bioadhesive effect due to the interaction with the negative charge of the sialic acid groups of the mucin.

The compositions of the invention may be administered to a mammal in suitable dosage forms and by means of a drug delivery device, all of which are known per se and include, for example, a capsule, a powder, or a compressed tablet to be administered orally and dissolved in the stomach to release bioadhesive particles. Said compositions may be administered together with a suitable liquid (such as water).

Pharmaceutically active agents which may be included in the compositions of the invention are those suitable for the topical treatment of gastric disorders, as well as compounds that typically exhibit limited absorption in the gastrointestinal tract due to limited absorption in the small intestine. Active compounds which are useful in treating diseases intervening stomach are useful for the treatment of H. pylori infection, as well as H ₂ -antagonizující agents and proton pump inhibitors. The following is an exemplary and non-limiting list of substances that may be considered in this regard: metronidazole, ampicillin, doxycycline, tetracycline, oxytzetracycline, intraconazole, ranitidine, cimetidine, famotidine, nizatidine and omeprazole.

Pharmaceutically active substances having advantageous absorption in the small intestine and useful in the compositions of the invention can be found in all therapeutic categories. The following is an exemplary and non-limiting list of such active ingredients: levodopa, methyldopa, furosemide, carvedilol, atenolol, topiramate, hydrochlorothiazide, captopril and orlistat (and other active ingredients for the treatment of obesity).

Combinations of the above therapeutic agents / active agents can also be used.

• 4

4

4 4

I 4 4 4 4

4 »4

4

For the avoidance of doubt, the term therapeutic agent herein means an agent suitable for use in the treatment and prevention of diseases.

The compositions of the invention may be used to treat or prevent diseases or conditions in mammalian patients. For the exemplary and non-limiting list of pharmaceutically active substances mentioned above, mention may be made of those diseases or conditions known to be treatable by these active substances, and in particular those diseases and conditions specifically mentioned in connection with the aforementioned active substances in Martindale. , The Extra Pharmacopoeia, 31st Ed., Royal Pharmaceutical Society (1996).

The amount of therapeutic agent that can be used in the compositions of the invention will depend on the particular therapeutic agent used and the particular disease to be treated, but will be in the range of 0.1 to 10 g. the dosage of the therapeutic agents can be determined routinely. For example, the dosage estimate may be derived from the dosage of known injectable products, provided that 0.1 to 100% of the administered dose is absorbed.

Suitable single unit doses may thus be from 100 micrograms to 1000 milligrams, depending on the particular therapeutic agents administered and the mode of administration. Suitable daily dosages are 100 micrograms to 5 grams / day, depending on the therapeutic agents administered.

The compositions of the invention may be administered one or more times (e.g., three times) per day, depending on the condition being treated.

The compositions of the invention may also contain other ingredients in the form of pharmaceutical excipients such as preservatives (for example low concentrations of substances such as sodium pyrosulfate),

Átory φ stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabiliz stabilizφ phospholipids and enzyme inhibitors.

An advantage of the compositions of the invention is that they may have significant retention in the empty stomach of mammals (e.g., humans), may contain a high content of water-soluble and fat-soluble pharmaceutically active substances, while guaranteeing the controlled release of said pharmaceutically active substances over a period of time. in accordance with clinical need.

In addition, the compositions of the invention also have the advantage that they can be used when assisting the retention of pharmaceutical agents in the stomach of a mammal in the topical treatment of gastric diseases or improving the intestinal absorption of active substances having limited absorption capacity in the small intestine of mammals.

A further advantage of the compositions of the invention is that they can be prepared using established pharmaceutical procedures and materials that are approved for use in food or pharmaceuticals or have other similar status.

According to a further feature of the invention there is provided a method of treating or prophylaxis of a disease, comprising administering to a patient in need thereof a composition of the invention comprising a therapeutic agent effective against said disease.

In the following, the invention is illustrated in a non-limiting manner by way of examples of a specific embodiment thereof, examples 1 to 4 being intended to demonstrate that when certain procedures are used, some of which are described in the prior art, microspheres with the desired properties. The following examples (5-7) illustrate the invention in which gastroretentive controlled release microspheres are prepared using a novel combination process comprising emulsification and spray drying (water-in-oil-in-water emulsion ( w / o / w) and oil-in-water emulsions (o / w)]. Example 8 demonstrates that the compositions of the invention exhibit improved gastric retention in human patients.

The examples relate to the drawings in which:

Fig. 1 shows the release profile of the active ingredient from cimetidine-containing microparticles, these microparticles being obtained by a combined w / o emulsion spray-drying method;

Fig. 2 shows the release profile of the active ingredient from nizatidine-containing microparticles, these microparticles being obtained by a combined o / w emulsification and spray drying method;

Fig. 3 shows the profile of the microparticles containing the microparticles obtained by the release of cimetidine, the combined active ingredient from the method of emulsification w / o / w and spray drying;

Fig. 4 shows the release profile of the active ingredient from famotidine-containing microparticles, which microparticles were obtained by a combined w / o / w emulsion spray-drying method; and Fig. 5 is a histogram illustrating gastric emptying of microspheres containing disodium clondronate tetrahydrate containing microspheres obtained by a combined w / o / w emulsion spray drying method.

9 9 4

4 • 444 444

9 9

9999

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of non-cross-linked chitosan microspheres

0.3 to 0.4 grams of chitosan hydrochloride (available from Norwegian company under the tradename Seacure CL 210) is weighed into a 50 ml beaker and 20 ml of water is then added to the beaker to dissolve the chitosan. The volume of the solution obtained is made up to 100 ml with water and the solution is used in the spray-drying process. Co-current spray drying was performed using a SD-04 spray dryer (Lab Plant, UK) with a standard nozzle of 0.5 mm. The inlet temperature was maintained at 160 ° C. The spray solution flow rate was set to 6 ml / min. The compressed air flow (measured by the inlet air volume) was set to 10 l / min. The particles obtained have good sphericity, determined photomicroscopically (Nikon Optiphot) at 20 or 40 times magnification, and have a mean size equal to 6 microns [mean volume diameter (MVD) as measured by laser diffraction method (Malvern Mastersizer Model MS 1002)]. The obtained particles carry a positive zeta potential (surface charge) of +27 mV, as determined in 0.001 M acetate buffer at pH 4.0 using a Malvern Zetasizer mark IV. For this measurement, 1-3 mg of microspheres are dispersed in said buffer system.

However, it has been found that the microspheres prepared in this manner swell in water and dissolve rapidly in buffer at pH 2.0 (stomach conditions). Such particles would therefore have a short half-life in the stomach and would therefore not exhibit a controlled release capability or gastroretention.

9 9 99

989 99 9

Example 2

Preparation of cross-linked chitosan microspheres without a rate-controlling layer using spray drying

In order to obtain stable, non-swellable and non-swellable chitosan microspheres, microspheres without a pharmaceutically active agent were prepared by spray drying using formaldehyde and glutaraldehyde as crosslinking agents.

In this case, the procedure of Example 1 is repeated except that a defined amount of aqueous formaldehyde or glutaraldehyde solution is added to the chitosan solution prior to spraying. The chitosan concentration is 0.1%. Defined amounts of crosslinking agent were 0.5, 1.0, 2.0, 4.0 and 8.8 ml of 1% formaldehyde solution and 0.5, 1.0, 1.5, 2.0, 4.0, 8.0 and 16.0 ml of 1% glutaraldehyde solution.

The microspheres thus prepared have good sphericity. The size of the microspheres prepared using the formaldehyde crosslinking agent ranges from 1.75 to 3.2 microns (MDV), with a zeta potential measured in 0.001M acetate buffer at pH 4 ranging from +16 to +20 mV. The greater the amount of crosslinking agent used, the lower the potential of zeta microspheres. Using glutaraldehyde crosslinking systems, the microspheres have an MVD ranging from 1.5 to 3.7 microns and a zeta potential ranging from +21 to +14.5 mV; as in the previous case, the greater the amount of crosslinking agent used, the lower the zeta microspheres potential. When a 0.2% chitosan solution and the same amount of glutaraldehyde are used, the microspheres still have good spheres but are somewhat larger in size (this size ranges from 8.8 to 2.3 microns (MDV)). The zeta potential of these microspheres is the same as the microspheres obtained using a 0.1% chitosan solution. These microspheres do not contain a pharmaceutically active agent. Next, the same microspheres will be prepared but containing the pharmaceutically active agent.

Example 3

Preparation of microspheres containing a pharmaceutically active agent using spray drying

These microspheres were prepared by a procedure similar to that described in Example 2.

To 500 ml of a 0.1% aqueous chitosan solution or to 250 ml of a 0.2% aqueous chitosan solution is added 10 mg of cimetidine. A specific amount of 2% glutaraldehyde aqueous solution or 1% formaldehyde aqueous solution is then added under magnetic stirring. Spray drying was performed under the conditions described in Example 1.

The microspheres obtained have the following properties. All microspheres are spherical. The active ingredient content of the microspheres is approximately 17% by weight. The microparticle size (MVD) ranges from 2.0 to 7.9 microns, depending on the initial chitosan concentration used (0.1% or 0.2%) and the amount of crosslinking agent added (1 to 4 mL of 4% glutaraldehyde) ). The zeta potential at pH 4.0 in 0.001M acetate buffer ranges from +15 to +17 mV. Similar results are obtained using formaldehyde as a crosslinking agent.

The content of the pharmaceutically active agent in the microspheres is measured as follows. An accurately weighed defined quantity of chitosan microspheres containing the active substance is placed in a 50 ml volumetric flask. The solid is dispersed and diluted to volume with 0.1N sulfuric acid. The resulting suspension is then sonicated in an ultrasonic chamber

99

9 9

9 9

999 999

9

9 9 9

9 9

9999 • 9 (Decon FS 100) for 10 minutes and stored overnight at room temperature to allow the active substance to completely release from the microspheres. Using a 0.2 micron syringe, 5 ml of the suspension is filtered to separate the solids and absorbance is determined in the filtrate. The active substance content is measured by spectrophotometry.

The in vitro release of the active ingredient is determined as follows. The in vitro test is performed using a Copley-Erweka DT-6 dissolution apparatus with a USP Apparatus 2 or BP Apparatus 11 vane agitator. The samples are suspended in 300 mL phosphate buffered saline (pH 7.4) at 37 ° C. at a rotation speed of the stirring system of 50 rpm. A specific, accurately weighed amount of microspheres containing the active ingredient is placed in each vial. 3 ml samples are then withdrawn by syringe at predetermined intervals. The same amount of fresh dissolution medium is always added to the system. The samples are filtered and the active substance content is determined spectrophotometrically. The pure, unincorporated free drug was used as a control. Dissolution measurement shows that the release of the H ₂ -antagonist from chitosan microspheres prepared by spray drying was extremely rapid. Most of the pharmaceutically active agent was released in less than 15 minutes and the dissolution profile in this case was essentially the same as the dissolution profile of the free active agent not incorporated in the microspheres.

Thus, although cross-linked chitosan microspheres having a small particle size and positive charge and containing an acceptable amount of a pharmaceutically active agent can be prepared, the release of the active agent incorporated in these microspheres is very rapid and the microspheres thus prepared are of no value for clinical application.

AAA AA · AAA *

AA * A

A AAAA * A * * ··· AAA

AAA AAA AAA ** A AA * A

Example 4

Preparation of controlled release microspheres using a water-in-oil emulsion process followed by spray drying

It is clearly apparent from the examples that only the stabilized chitosan microspheres described in the prior art are not suitable for gastroretentive systems providing controlled release of the active ingredient. In order to delay the release of the active ingredient, an alternative emulsion process using ethylcellulose as a retention agent has been investigated. The water-soluble pharmaceutically active substance is first dissolved in gelatin to provide a cross-linking agent and a physical structure within the microspheres obtained by spray drying.

Weigh 0.1 g of gelatin A and 0.1 g of the pharmaceutical active substance (cimetidine or famotidine) into a 16 ml tube. 5 ml of distilled water are then added to the tube. After heating the mixture to 60 ° C, a clear solution was obtained.

In a 100 ml beaker, 0.4 g of water-insoluble polymeric ethylcellulose (EC-Dow) is dissolved in 50 ml of dichloromethane. The aqueous solution containing the pharmaceutically active ingredient and gelatin is added dropwise to the oily phase with stirring. The system is then homogenized for 2 minutes at 11,000 rpm. The water-in-oil emulsion (W / o) thus formed is spray dried directly under the following conditions: co-spray spray drying is performed using an SD-04 spray dryer (Lab Plant, UK) with a standard 0.5 mm nozzle. The inlet temperature was maintained at 50 ° C. The spray fluid flow was set at 8 ml / minute.

9 9 9 9 9 9 9 9 9

Table 1

Characteristics of microparticles prepared by the combined w / o emulsification and spray drying method

Active substance Content effectively substances (%) Size (pm) Zeta potential (mV; pH 7) ⁺ Cimetidine 15.5 6.04 -4.0 Famotidine 12.8 10,09 -3.3

+) Ο, ΟΟΟΙΜ phosphate buffer

Table 1 above shows the physicochemical characteristics of the particles prepared by the combined w / o emulsion and spray drying method. These particles have poor sphericity. The particle size is 10 microns. Since no positively charged material was used in this example, the thus prepared particles are negatively charged.

Determination of the dissolution profile of the release of the active ingredient from the microparticles prepared by the combined w / o emulsification and spray drying method was performed in the dissolution apparatus described above. The release profile of the cimetidine contained in the microparticles prepared by said combined w / o emulsification and spray drying method is shown in Fig. 1. The release of cimetidine from the particles is greatly delayed compared to the release of the active ingredient from the microspheres prepared by conventional spray drying as described in Example 1. The active ingredient was gradually released over several hours.

The microparticles were observed to float at the dissolution medium level. Addition of a wetting agent to

9 9 · 9

9999 ·

9999 9

9

9 9 9

9

9 9

9

999 999

99 • 9 9

The dissolution medium in the form of 0.05% Tween 80 initiated an increase in the release rate of the active ingredient.

Example 5

Preparation of controlled release microspheres by the oil-in-water (o / w) emulsion method a. followed by spray drying

In cases where the active ingredient is sufficiently soluble in an organic solvent, it is possible to prepare microspheres containing the active ingredient using an oil-in-water emulsion. In this case, the oil phase containing the active ingredient and ethylcellulose (or other suitable release controlling polymer) is dispersed in an aqueous chitosan solution and the resulting dispersion is spray dried. This method can be demonstrated using the H ₂ -antagonizing agent formed by nizatidine.

0.1 g of nizatidine and 0.2 g of ethylcellulose are dissolved in 5 ml of dichloromethane in a 16 ml tube. The solution obtained is added dropwise to 100 ml of a 0.4% aqueous chitosan solution under magnetic stirring. The homogenization is carried out for 1 minute at 12,500 rpm and then subjected to ultrasound if necessary. After addition of 2 ml of a 4% aqueous glutaraldehyde solution, the emulsion obtained is spray dried. Co-current spray drying is performed in a SD-04 spray dryer (Lab Plant, UK) with a standard 0.5 mm nozzle. The inlet temperature is set at 13 ° C, the spray fluid flow is set to 6 ml / min and the air flow is set to 10 1 / min. The sphericity of the microparticles containing the pharmaceutically active agent is good. The particle size of the MVDs is 7.7 microns. The zeta potential at pH 4.0 and the ionic strength of 0.0002 M is + 9.0 mV. The active substance content in the microspheres is 8.4% by weight.

• · · · · · · ···· €

The release of the drug was measured using the USP dissolution method described in Example 3. The concentration of nizatidine was measured by the ultraviolet spectroscopic method at 313 nm as described by Wozniak in Analytical Profiles of Drug Substances, 19, ed. K. Florenz, Academic Press, San Diego, pp. 379-990. A controlled drug release profile was achieved (Fig. 2).

Example 6

Floating microsphere formulation prepared by new combined emulsion w / o / w method and spray drying

The chitosan microspheres prepared by the conventional spray drying process described in Example ¹ , in Example 3, have good sphericity and are positively charged. However, the rate of release of the H ₂ -antagonizing agent from the microspheres is rapid, accompanied by an eruptive effect. The release of the active ingredient from the microparticles prepared by the w / o emulsification and spray drying method described in Example 4 is retarded, but the particles do not have the ability to gastroretence. Positively charged microspheres are prepared as follows.

Weigh 0.1 g of gelatin type A and 0.1 g of water-soluble pharmaceutically active substance (cimetidine or famotidine) into a 16 ml tube. 5 ml of distilled water are then added to the tube. After heating the contents of the tube to 60 ° C, an aqueous phase is obtained consisting of a clear solution. This phase will hereinafter be referred to as the internal phase. The oily phase consists of 0.2 g of ethylcellulose (Dow) dissolved in 25 ml of dichloromethane in a 50 ml beaker. The outer phase consists of 150 ml of a 0.3% aqueous solution of chitosan (molecular weight 140,000 to 160,000) in a 200 ml beaker.

Said inner phase is added dropwise to the oil phase under magnetic stirring. The system is then homogenized using a Silverson homogenizer.

A (Silverson, Chesham, Bucks, UK) at 11,000 rpm for 2 minutes. If necessary, the mixture is sonicated. This primary emulsion is then added dropwise to the external aqueous phase under magnetic stirring. Further homogenization is performed at 10,000 rpm for two minutes. Before spray drying, 2 ml of 4% glutaraldehyde is used as a crosslinking agent. Co-current spray drying is performed using a SD-04 spray dryer (Lab Plant, UK) with a standard 0.5 mm nozzle. The inlet temperature is set at 150 ° C and the spray fluid flow is set at 6 ml / min. The active compound-free microspheres are prepared in the same manner by avoiding the use of a pharmaceutically active agent in the above process.

The characteristics of the drug-free microspheres prepared by the w / o / w and emulsion spray-drying method are shown in Table 2 below. a suitable dissolution medium (USP-simulated gastric scanning microscope can be observed that the particles are hollow after breakage, demonstrating the low density and the ability of the particles to float. A very fluid has been formed). In microspheric photomicroscopy, a good w / o / w emulsion, as evidenced by observations showing that the oil particles contain water droplets. The droplet size of the w / o / w emulsion and the isolated microspheres depends on the speed of mixing and the position of the nozzle arrangement in the spray drier. Rapid agitation (or ultrasound) results in smaller particle size. Larger microspheres are produced by countercurrent spray drying. The particles formed have a diameter of about 20 to 40 microns.

After removal of the solvent from the emulsion by evaporation, the particle size is reduced to about 10-15 microns. For • 0 4 · * ··· «>

0 0 00 00 0000

000 0 0 0000

4444 44 44 944 444

0 0 · · ♦

0000 0 000 000 0 · 0 · To prepare microspheres with a size of 10 microns and the ability to swim, a process is used wherein the mixing speed of both the primary and secondary emulsions is set to 12,600 rpm and stirring is performed for 1 minute, followed by conventional co-current spray drying.

The characteristics of the thus prepared microspheres containing the pharmaceutically active agent are given in Table 3. The particle size is similar to that of the active agent-free microparticles. The particles are positively charged and have a high active substance content. The sphericity of the particles is acceptable.

An in vitro assay determining the release profile of the drug was performed using a dissolution device as described above. A dissolution paddle system (USP Apparatus 1 or BP apparatus 1) was used in this test. The microspheres were filled into hard gelatin capsules. The samples were weighed individually into capsules and thus introduced into 300-500 ml phosphate buffered saline at pH 7.4 containing different amounts of Tween 80 surfactant (which was used to evaluate the effect of the amount of wetting agent on the release rate). The temperature was set at 37 ° C and the rotation speed was set at 50 rpm. At predetermined intervals, 3 ml samples were withdrawn by syringe. An equal amount of fresh dissolution medium was always supplied to the system. Samples were filtered using 0.2 µm filters. The contents of the pharmaceutically active substance were determined by spectrophotometry.

Table 2

Characteristics of microspheres not containing a pharmaceutically active substance and prepared by the w / o / w emulsification method and spray drying

31 • · V, · 9,999 99 · 9 9 9 9 9 9 9 9 9 9 * 999 > 9999 99 99 999 999 9 9 9 9 9 9999 9,999,999 9 · 99 Mixing of emulsion speed / time Size of particles emulsion w / o / w (μιπ) Size Flotation Microsphere properties (pm)

PrimarySecondary

12600 / 1 min 12600 / 1 min smaller than 20 May 9, 71 X 12600 / 30 p 12600 / 30 p 40-80 16.41 X X 12600 rpm ⁺ 12600 / 30 S 5-10 7.71 X 12600 / 1 min 12600 / 30 p 20-40 20,93 ⁺⁺ X

+) ultrasonication in the case of a primary emulsion; ++) countercurrent spray drying; x good flotation properties; χχ excellent flotation property.

Table 3

Characteristics of the microspheres containing the pharmaceutically active substance prepared by the w / o / w emulsification method and spray drying.

Effective Content effectively Size Zeta potential substance substances (%) Added Found (pm) (mV) (pH 4) Cimetidine 13.3 12.7 11, 68 +13.4 Cimetidine 15, 5 12.7 9.58 + 13.0 Famotidine 13.2 13, 1 14.44 + 10.2 Famotidine 5.5 3, 8 11.57 + 11.0 Relaxation cimetidine and famotidine of floating chitosan microspheres were tested in the dissolution environment, phosphate buffered physiological

solution (PBS) and gastric fluid simulating fluid (SGF), in the presence of varying amounts of a wetting agent consisting of Tween 80. The results are shown in Figures 3 and 4. All microspheres release the active ingredient slowly, even in the case of a wetting agent.

Example 7

Preparation of floating microspheres prepared by new emulsion w / o / w method and spray drying without addition of crosslinking agent

Weigh 4 g of chitosanglutamate (SeaCure G210, Pronova) into a 1 liter graduated flask and dissolve the contents of the flask in approximately 600 ml of deionized water. Make up the volume of the flask to 1 liter with water. 2.4 g of ethylcellulose (45 cps, Dow) were dissolved in 120 ml of dichloromethane. Weigh 0,6 g of gelatine A (175 bloom, Croda) into a 20 ml graduated flask and dissolve the contents of the flask in approximately 15 ml of deionised water and f. · • • 4 · φ ··· * ···· # · · 9 999 999

9 · 9 9 9 9999 9 999 9 99 99 99 heats to approximately 50 ° C. The contents of the flask are then made up to 600 ml with water. 12.6 g of disodium clodronate tetrahydrate are weighed into a beaker and the contents of the beaker are dissolved by adding 20 ml of gelatin solution. 600 ml of chitosan solution is transferred to a 1 liter beaker and cooled in an ice bath for at least 5 minutes.

The gelatin-clodronate solution and 120 ml of ethylcellulose solution are transferred to a 250 ml beaker. The mixture was emulsified for 1 minute using a Silverson homogenizer (model L4R) set at 10,000 rpm to give a water-in-oil emulsion. The beaker is stored in an ice bath during emulsification to prevent the emulsion from overheating.

The obtained water-in-oil emulsion (gelatin / clodronate-ethylcellulose) is added to 600 ml of chitosan solution and emulsified for 1 minute at 10,000 rpm using a Silverson homogenizer to give a water-in-oil emulsion i-ve -Water.

The obtained water-in-oil-in-water emulsion is immediately spray dried using a Lab Plant SD-05 set as follows: inlet temperature 169 ° C, outlet temperature 79 ° C, air pressure 0.19 MPa and air flow 22 units . The emulsion is pumped into the apparatus by a Cole-Parmer peristaltic pump set at 11 ml / minute. The total drying time is about 70 minutes.

After drying, a fine white powder having a mean particle size in the range of 5 to 10 µm (determined by photomicroscopic measurement) is obtained. The yield of the whole process is about 20 to 40%.

The clodronate content of the dried powder was determined using gas chromatography (GC-MS). The formulation contains 60% by weight of anhydrous disodium clodronate.

• 0 «0» 0 0 0

000 000 • 0 0 0 0 0

0 0 · · · · · · ·

0 0 0 0 0 0 0

0 ♦ ·

0000 «000 000

The obtained spray dried powder was filled into size 0 hard gelatin capsules at 238 mg / capsule for administration to a human patient.

The release of the active ingredient from the filled capsules was measured using EP / USP method 2. One capsule was introduced into each dissolution vessel containing 900 ml of a 0.01 M hydrochloric acid test medium. All vessels are agitated with a paddle stirrer set at 100 rpm. The dissolution medium samples are withdrawn at regular intervals over 4 hours and the clodronate content is determined by gas chromatography (GS-MS). Upon completion of the test, the capsule shells are dissolved and the released powder floats at the dissolution medium level. It was found that 25% of the active ingredient was released within 150 minutes.

Example 8

Gastroretence measurement in human patient

The formulation of gastroretentive microspheres described in Example 7 was evaluated in a group of 9 healthy 50-70 year olds fasted (fasted). The administered formulation was radiation-labeled with a gamma (indium ¹¹¹ ) emitting radionuclide by adding a small amount of ion exchange resin to the formulation. As a control, a gastric emptying simple liquid formulation indicator consisting of a technetium-99m labeled solution of diethylenetriaminepentaacetic acid (DTPA) was used. Subjects were co-administered with microspheres (0.5 MBq) and said control solution. The pellets (contained in a hard gelatin capsule) were administered with a solution of DTPA in 200 ml of water.

The test subjects were then placed in front of the Garrana camera (GE-Maxi camera), recording the initial and "44" 4 "44 44 4 4 · 4 • 44 4 4" 444

444444 4 4 4 444444

4 4 4 · 4 ··· «4 444 444 4« 44 subsequent images at two energy levels to monitor both radionuclides. Images were taken every 15 minutes within 6 hours of both formulations. 2 hours after the administration of these formulations, the subjects ingested a drink consisting of 200 ml of water. The obtained images were then analyzed by a standard method (geometric center calculation) to obtain a gastroretentive and gastric emptying profile. The results obtained are presented in the form of a bar chart in FIG.

This bar chart very well demonstrates the dramatic difference between gastroretence of gastroretentive microspheres and gastroretence of control solution. At all selected times, the control solution is emptied from the stomach to a much greater extent than that of gastroretentive microspheres.

Claims (25)

A composition for delivering a controlled release pharmaceutical agent in a stomach environment for a prolonged period of time, comprising a microsphere comprising the active agent in an inner core of the microsphere, and (i) a rate controlling layer of the water-insoluble polymer; and (ii) an outer layer of bioadhesive. agents in the form of a cationic polymer. Composition according to claim 1, characterized in that the cationic polymer is a cationic polysaccharide, a cationic protein or a synthetic cationic polymer. Composition according to claim 1 or 2, characterized in that the inner core comprises a gelling hydrocolloid. Composition according to any one of the preceding claims, characterized in that the water-insoluble polymer is ethylcellulose. Composition according to any one of the preceding claims, characterized in that the cationic bioadhesive agent is chitosan. Composition according to any one of claims 1 to 4, characterized in that the cationic bioadhesive agent is diethylaminoethyldextran. • · · · · · Composition according to any one of claims 3 to 6, characterized in that the gelling colloid is gelatin. Composition according to any one of the preceding claims, characterized in that it is prepared by spray-drying an oil-in-water emulsion or a water-in-oil-in-water emulsion containing the components of the composition. Composition according to any one of the preceding claims, characterized in that the active substance is intended for the topical treatment of stomach disease. Composition according to any one of claims 1 to 8, characterized in that the active substance has a limited absorption capacity in the small intestine of the mammal. Composition according to one of Claims 1 to 9, characterized in that the active ingredient is intended for the treatment of Helicobacter pylori infection. Composition according to one of Claims 1 to 9, characterized in that the active substance is intended for the treatment of Campylobacter pylori infection. Composition according to one of Claims 1 to 9, characterized in that the active ingredient is a H ₂ -antagonizing agent or a proton pump inhibitor. Composition according to one of Claims 1 to 9, characterized in that the active substance is a bisphosphonate. Φ Φ · · · · · · φ · φ · φ · φ · φ · Φ ΦΦΦΦΦ Φ · · ·· · Φ Φ Φ · · · · Φ Φ ΦΦΦ ΦΦΦ Φ ΦΦ A pharmaceutical formulation in a form suitable for oral administration comprising a composition according to any one of claims 1 to 14 in a pharmaceutically acceptable dosage form. Use of a composition according to any one of claims 1 to 14 or a pharmaceutical formulation according to claim 15 as a means of delivering a therapeutic agent to the stomach. 17. Use of a composition according to any one of claims 1 to 14 or a pharmaceutical formulation according to claim 15 for gastroretention of the active ingredient. 18. A method of achieving gastroretence comprising administering to a patient a composition according to any one of claims 1 to 14 or a pharmaceutical formulation according to claim 15. 19. A method of treating or prophylaxis of a disease comprising administering to a patient in need of such treatment or prophylaxis a composition according to any one of claims 1 to 14 or a pharmaceutical formulation according to claim 15 comprising an active ingredient that is effective against said disease. 20. The method of claim 19, wherein the disease is a stomach disease and the active ingredient of the composition or pharmaceutical formulation is an active ingredient for topical treatment of said disease. A method of improving gastrointestinal absorption of an active agent having limited ability to absorb in a thin manner An intestine comprising administering to a patient a composition according to any one of claims 1 to 14 or a pharmaceutical formulation according to claim 15 comprising said active ingredient. The use of a composition according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment or prophylaxis of a disease which, resp. comprising administering said composition comprising a therapeutic agent effective against said disease to a patient in need of such treatment or prophylaxis. Use of a composition according to any one of claims 1 to 14 in the manufacture of a medicament for use in a method of treatment according to any one of claims 18 to 21. A kit for use in treating an H.pylori infection comprising a composition comprising an H ₂ -antagonizing agent, a proton pump inhibitor or an antacid, and a composition according to claim 11. A method of preparing a composition according to any one of claims 1 to 14, comprising spray drying an oil-in-water emulsion or a water-in-oil-in-water emulsion comprising the components of the composition.