WO2010003430A1

WO2010003430A1 - Formulations with polycarbohydratesiloxane coatings, their production and use

Info

Publication number: WO2010003430A1
Application number: PCT/EP2008/005520
Authority: WO
Inventors: Axel Thierauf; Jörg NEEMANN
Original assignee: Pethylation Gmbh
Priority date: 2008-07-07
Filing date: 2008-07-07
Publication date: 2010-01-14
Also published as: WO2010003645A1

Abstract

The present invention provides a polycarbohydratesiloxane (PCS) coating, a formulation comprising one ore more active ingredient units coated with PCS, which is effective to confine the release of the active ingredient unit to the duodenal or intestinal region of the digestive tract. The invention provides methods for producing such pharmaceutical formulations and their use.

Description

Formulations with Polycarbohydratesiloxane Coatings, their production and use

Background of the Invention

The delivery of active ingredients, in particular pharmaceuticals, to humans and animals can occur via various routes including topical, enteral, and parenteral. The predominantly used administration routes are the non-invasive enteral or topical administration routes, in particular via the oral route using, e.g. tablets, pills, capsules, syrups, suspensions or the like. Oral administration provides ease of use, since the active ingredient can be administered without the need for the presence of a clinical practioner, which is commonly required for all parental administrations, and relatively low costs. Accordingly, the market for orally administered pharmaceuticals represents the largest product segment of the pharmaceutical industry. Some companies believe that the potential market for many drugs could be significantly expanded, if novel delivery systems are developed for therapeutics that are currently only available as injectable. The market for orally administered drugs is a rapidly expanding area of drug delivery and oral delivery is the safest, most convenient and most economical means of administering active ingredients. However, some drugs, in particular protein and peptide drugs can not be reliably delivered via the oral route due to degradation in particular in the stomach other drugs like, e.g. NSAIDs, cause intestinal bleeding due to premature release in the stomach. Additionally, some drugs are difficult to formulate for oral administration due to their hydrophobicity. Accordingly, certain drugs, in particular protein drugs, including insulin, antibodies, growth hormones, peptides or proteins for vaccinations, are administered parenterally.

Thus, there is a need in the art to provide a safe and secure carrier system for active substance delivery to the gastrointestinal tract. Summary of the Invention

In a first aspect the present invention relates to a formulation comprising one ore more active ingredient units coated with a polycarbohydrateoxysiloxane (PCS).

In a second aspect the present invention relates to a method for producing a PCS coating comprising the steps:

(a) carrying out a first hydrolysis condensation reaction (HCR) of one residue X of one or more identical or different Si-compounds of the following formula (I)

SlXmYn

(I) wherein X is the same or different and selected from hydroxyl or -OR, optionally substituted, Y is hydrogen, m is 2, 3, or 4, n is 0, 1, or 2 and m + n = 4, in a water comprising solvent;

(b) carrying out a second HCR, wherein the material obtained in step (a) is reacted while removing the solvent until a cyclicRO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-X is formed wherein n is 3, 4 or 5 and x is 1, 2 or 3; and (c) carrying out at least a third HCR, wherein the material obtained in step (b) is reacted to obtain a maturated PCS, wherein R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted.

In a third aspect the present invention relates to a PCS coating producible by the method of the present invention.

In a fourth aspect the present invention relates to a method for producing a formulation comprising one or more active ingredient units comprising the steps of the method for producing a PCS coating and further comprising the step:

(d) applying the material obtained at the end of step (b) or the material formed during step (c) to the surface of an active ingredient unit. In a fifth aspect the present invention relates to a method for producing a formulation comprising one or more active ingredient units comprising the steps:

(a) providing cyclo RO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-_X, wherein n is 3, 4 or 5 and x is 1, 2 or 3 and R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted or a matured PCS derived therefrom by at least one further HCR and

(b) applying the material to the surface of an active ingredient unit.

In a sixth aspect the present invention relates to a formulation producible by the method of the present invention.

In a seventh aspect the present invention relates to a formulation of the present invention for medical use.

In a eight aspect the present invention relates to the use of a PCS coating to protect active ingredient units from degradation and/or dissolution in acidic environment.

Detailed Description of the Invention

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H. G. W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland). Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

To overcome problems associated with prior art formulations comprising active ingredients the present invention provides a formulation comprising, essentially consisting or consisting of one ore more active ingredient units coated with a polycarbohydrateoxysiloxane (PCS). The formulations of the present invention are preferably for oral administration, i.e. they are formulated as oral dosage forms, e.g. tablets, caplets, pills, hard or soft capsules, lozenges, sachets, pastilles, micro-pills, granules, beads, pellets, micro pellets, syrups, suspensions, and mini-tablets. The PCS coating provides several advantages over prior art coating. These advantages comprise extremely good wettability of active ingredient surfaces. This advantage also extends to active ingredients that are poorly-wettable or non-wettable due to their hydrophobicity as are many proteins, peptides or small molecular compounds, i.e. compounds that typically have a molecular weight of less than 2000 g/mol. This advantage is due to the hydrophobicity of PCS outside the alimentary tract, that is primarily mediated by the carbohydrate side chains of the oxysiloxanes.

Once in contact with aqueous solutions the PCS coating forms an inner and outer surface on the active ingredient. At the inner surface the active ingredient remains completely wetted by the hydrophobic PCS coating. At the outer surface the PCS coating converts to mostly silanol (Si-OH Bonds), which is hydrophilic and facilitates solubilisation of the active ingredient and has a high affinity to the walls of the small intestines. Silanol has similar chemical and physical properties as silica gel. However, this conversion of the outer surface of the coating does not lead to cracks in the coating, which remains fluid tight and does not allow synereses to occur. The fluid tight coating is maintained until the silanol dissolves, which occurs in the presence of Na⁺ and at elevated pH as encountered in the duodenum and in particular in the ileum, once the outer silanol layer dissolves the layer of PCS is hydrolyzed to silanol, which then dissolves. Thus, the outside of the coated active ingredient unit will stay hydrophilic during the solubilisation process, while the PCS at the inside and in particular the layer in direct contact with the active ingredient unit will stay hydrophobic. As outlined above the extend of the hydrophobicity will depend on the respective carbohydrate side chains and possible substituents. Due to the pH dependent solubility properties of silica gel (see Fig. 1 and Fig. 4), which is formed at least partially once the PCS coating contacts the aqueous gastrointestinal environment, the formulation provides a particularly advantageous controlled release pattern, since the siloxanol efficiently prevents the release of the active ingredient unit(s) in the acidic environment of the stomach and facilitates the release of the active ingredient primarily after the coated active ingredient unit has left the acidic stomach environment. On the other hand the inside of the coating contacting the active ingredient does not react to silanol and remains hydrophobic almost until the formulation disintegrates entirely. At around pH 6.0 the silanol starts to react to silica gel, which remains intact almost up to pH 8.0. The reaction is accelerated in the presence of Na⁺. The time required to dissolve the respective coating in the duodenum and preferably in the ileum will depend on the thickness of the PCS coating, the pH and the Na⁺-concentration. Thus, based on the teaching provided herein and using the standard tests developed in the art the skilled person can select a thickness of the PCS coating as required by the desired release pattern.

Accordingly, a further advantage provided by the PCS coating is a control of the release of the active ingredient unit in a pH dependent manner. This behavior at the acidic pH of the stomach and the almost neutral pH of the colon is depicted in Fig.4. The stomach is a region of high acidity (about pH 1 to 3). Specific glands and organs emptying into the small intestine raise the pH of the material leaving the stomach to approximately pH 5.0 to 6.0. The large intestine and the colon are about pH 6.4 to 8.0. The transit time through the small intestine is approximately three hours. In contrast, the transit time through the large intestine is approximately 35 hours. The PCS coating of the present invention provides a fluid tight or essentially fluid tight protection to the coated active ingredient in the pH environment of the stomach. It prevents diffusion of the active ingredient and/or synereses due to IEP. Thus, the PCS coating not only prevents disintegration of the coated active ingredient unit(s) comprised in the formulation but it prevents the release of the active ingredient. Preferably the PCS coating prevents the release of the active ingredient for at least 30 min under the conditions of the stomach, more preferably for at least 60 mins, more preferably for at least 90 mins, more preferably for at least 120 mins, more preferably for about 180 mins or more.

To test, whether the PCS coating is suitable to prevent the release of the active ingredient(s) from the active ingredient unit model fluids, which model the environment found in the stomach, can be used. Such model fluids are described in the respective Pharmacopoeias, e.g. European, Japanese or US pharmacopoeias. Similarly, test systems to test the dissolution behavior of a given formulation are described. An active ingredient is considered not to be released from the formulation, if less than 5% of the active ingredient is released from the formulation after the formulation has been incubated for at least 30 min, more preferably for at least 60 mins, more preferably for at least 90 mins, more preferably for at least 120 mins, more preferably for at least 180 mins in the disintegration method as described in Part I No. 14 of the Japanese Pharmacopeia (XIV Edition) using a basket-rack assembly and 1^st fluid as solvent that comprises 2.0 g sodium chloride and 7.0 mL HCl in a total of 1000 mL to provide a pH of about 1.2. Preferably, less than 2% of the active ingredient is released from the formulation after the formulation has been incubated for at least 30 min, more preferably for at least 60 mins, more preferably for at least 90 mins, more preferably for at least 120 mins, more preferably for at least 180 mins as outlined above. More preferably, less than 1% of the active ingredient is released from the formulation after the formulation has been incubated for at least 30 min, more preferably for at least 60 mins, more preferably for at least 90 mins, more preferably for at least 120 mins, more preferably for at least 180 mins as outlined above. Most preferably, less than 0.1% of the active ingredient is released from the formulation after the formulation has been incubated for at least 30 min, more preferably for at least 60 mins, more preferably for at least 90 mins, more preferably for at least 120 mins, more preferably for at least 180 mins as outlined above. To prevent the release of the active ingredient from the active ingredient unit, it is preferred that the coating does not comprise cracks or holes, which may allow access of the fluid to the coated active ingredient core. It is noted that according to US Pharmacopeia Edition XXIII an enteric coating is considered to be stable under acidic conditions if less than 10% of the active ingredient is released after 120 min in solution 1, which is equivalent to Japanese Pharmacopeia (XIV Edition) 1^st fluid (see "Drug release. Enteric-coated articles"). It is further required that more then 75% of the active ingredient are released once the enteric-coated article is shifted to pH 6.8, i.e. to solution 2 or 2^nd fluid. As indicated above the PCS coatings of the active ingredients of the formulations of the present invention are significantly more stable under conditions simulating the stomach environment then required by the US Pharmacopeia.

In a preferred embodiment of the formulation of the invention the active ingredient unit comprises, essentially consists or consists of one or more active ingredients, e.g. pharmaceuticals, minerals, vitamins and/or mixtures thereof, and optionally one or more excipient and/or release modifying substance.

The excipients comprised in the active ingredient unit include diluents (bulking agents), lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, flavoring agents, binding agents, excipient supports, glidants, permeability enhancement excipients, plasticizers and the like, all of which are known in the art; all named excipients are optional components. It will be understood by those in the art that some substances serve more than one purpose in a pharmaceutical composition. For instance, some substances are binders that help hold a tablet together after compression, yet are disintegrants that help break the tablet apart once it reaches the target delivery site. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

Binders are used to impart cohesive qualities to the active ingredient unit, and thus ensure that the active ingredient remains intact, e.g. after compression to form a tablet. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatine, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like), veegum, carbomer (e.g. carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g. KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binding agents also include acacia, agar, alginic acid, cabomers, carrageenan. cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein. The binding agent can be, relative to the active ingredient, in the amount of about 2% w/w of the active ingredient; about 4%, w/w of the active ingredient, about 6%, w/w, of the active ingredient, about 8%, w/w, of the active ingredient; about 10% w/w of the active ingredient; about 12%, w/w of the active ingredient; about 14%, w/w, of the active ingredient, about 16%, w/w/, of the active ingredient; about 18% w/w of the active ingredient; about 20%, w/w of the active ingredient, about 22%, w/w, of the active ingredient, about 24%, w/w, of the active ingredient; about 26% w/w of the active ingredient; about 28%, w/w of the active ingredient, about 30%, w/w, of the active ingredient, about 32%, w/w, of the active ingredient; about 34% w/w of the active ingredient; about 36%, w/w of the active ingredient, about 38%, w/w, of the active ingredient, about 40%, w/w, of the active ingredient; about 42% w/w of the active ingredient; about 44%, w/w of the active ingredient; about 46%, w/w, of the active ingredient, about 48%, w/w/, of the active ingredient; about 50% w/w of the active ingredient; about 52%, w/w of the active ingredient, about 54%, w/w, of the active ingredient, about 56%, w/w, of the active ingredient; about 58% w/w of the active ingredient; about 60%, w/w of the active ingredient, about 62%, w/w, of the active ingredient, about 64%, w/w, of the active ingredient; about 66% w/w of the active ingredient; about 68%, w/w of the active ingredient, about 70%, w/w, of the active ingredient, about 72%, w/w, of the active ingredient; about 74% w/w of the active ingredient; about 76%, w/w of the active ingredient; about 78%, w/w, of the active ingredient, about 80%, w/w/, of the active ingredient; about 82% w/w of the active ingredient; about 84%, w/w of the active ingredient, about 86%, w/w, of the active ingredient, about 88%, w/w, of the active ingredient; about 90% w/w of the active ingredient; about 92%, w/w of the active ingredient, about 91%, w/w, of the active ingredient, about 96%, w/w, of the active ingredient; about 98%, w/w, of the active ingredient, or more, if determined to be appropriate.

Diluents are typically necessary to increase bulk so that a practical size active ingredient and/or formulation of the invention are ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g. AVICEL), micro fine cellulose, pregelitinized starch, calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include ammonium alginate, calcium carbonate, calcium phosphate, calcium sulphate, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glycerol palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, malt dextrin, maltose, medium- chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powered cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-β-cyclodextrin, talc, tragacanth, trehalose, and xylitol. Generally, diluents are used in amounts calculated to obtain a volume tablet or capsule that is desired; in some embodiments, a diluent is used in an amount of about 5% or more, about 10% or more, about 15% or more, 20% or more, about 22% or more, about 24% or more, about 26% or more, about 28% or more, about 30% or more, about 32% or more, about 34% or more, about 36% or more, about 38% or more, about 40% or more, about 42% or more, about 44% or more, about 46% or more, about 48% or more, about 50% or more, about 52% or more, about 54% or more, about 56% or more, about 58% or more, about 60% or more, about 62% or more, about 64% or more, about 68% or more, about 70% ore more, about 72% or more, about 74% or more, about 76% or more, about 78% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, weight/weight, of a active ingredient; between about 10% and about 90%, w/w of the active ingredient; between about 20% and about 80% w/w of the active ingredient; between about 30% and about 70% w/w of the active ingredient; between about 40% and about 60% w/w of the active ingredient.

Lubricants are used to facilitate active ingredient manufacture, e.g. tablet manufacture; examples of suitable lubricants include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, glycerine, magnesium stearate, calcium stearate, and stearic acid. Stearates, if present, in one embodiment represent at no more than approximately 2 wt. % of the active ingredient. Further examples of lubricants include calcium stearate, glycerine monostearate, glycerol behenate, glycerol palmitostearate, magnesium lauryl sulfate, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Disintegrates are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or cross linked polymers. Disintegrates also include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL, PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON, POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB) and starch. Additional disintegrates include alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, colloidal silicon dioxide, sodium croscarmellose, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium polacrilin, povidone, powdered cellulose, sodium alginate, sodium carboxymethyl cellulose, sodium starch glycolate, starch, and pregelatinized starch. The disintegrant can be, relative to the active ingredient, in the amount of about 1% w/w of the active ingredient, about 2% w/w of the active ingredient; about 3%, w/w/ of the active ingredient; about 4%, w/w of the active ingredient; about 5%, w/w/ of the active ingredient, about 6%, w/w, of the active ingredient, about 7%, w/w, of the active ingredient, about 8%, w/w, of the active ingredient; about 9%, w/w, of the active ingredient; about 10% w/w of the active ingredient t; about 12%, w/w of the active ingredient; about 14%, w/w, of the active ingredient, about 16%, w/w/, of the active ingredient; about 18% w/w of the active ingredient; about 20%, w/w of the active ingredient, about 22%, w/w, of the active ingredient, about 24%, w/w, of the active ingredient; about 26% w/w of the active ingredient; about 28%, w/w of the active ingredient, about 30%, w/w, of the active ingredient, about 32%, w/w, of the active ingredient; between about 1% and about 10%, w/w of the active ingredient; between about 2% and about 8% w/w of the active ingredient; between about 3% and about 7% w/w of the active ingredient; between about 4% and about 6% w/w of the active ingredient.

Stabilizers (also called absorption enhancers) are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions. Stabilizing agents include d- Alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), acacia, albumin, alginic acid, aluminum stearate, ammonium alginate, ascorbic acid, ascorbyl palmitate, bentonite, butylated hydroxytoluene, calcium alginate, calcium stearate. calcium carboxymethylcellulose, carrageenan, ceratonia, colloidal silicon dioxide, cyclodextrins, diethanolamine, edetates, ethyl cellulose, ethylene glycol palmitostearate, glycerine monostearate, guar gum, hydroxypropyl cellulose, hypromellose, invert sugar, lecithin, magnesium aluminum silicate, monoethanolamine, pectin, poloxamer, polyvinyl alcohol, potassium alginate, potassium polacrilin, povidone, propyl gallate, propylene glycol, propylene glycol alginate, raffϊnose, sodium acetate, sodium alginate, sodium borate, sodium carboxymethyl cellulose, sodium stearyl fumarate, sorbitol, stearyl alcohol, sufobutyl-b- cyclodextrin, trehalose, white wax, xanthan gum, xylitol, yellow wax, and zinc acetate. The stabilizer can be, relative to the active ingredient, in the amount of about 1% w/w of the active ingredient, about 2% w/w of the active ingredient; about 3%, w/w/ of the active ingredient; about 4%, w/w of the active ingredient; about 5%, w/w/ of the active ingredient, about 6%, w/w, of the active ingredient, about 7%, w/w, of the active ingredient, about 8%, w/w, of the active ingredient; about 9%, w/w, of the active ingredient; about 10% w/w of the active ingredient t; about 12%, w/w of the active ingredient; about 14%, w/w, of the active ingredient, about 16%, w/w/, of the active ingredient; about 18% w/w of the active ingredient; about 20%, w/w of the active ingredient, about 22%, w/w, of the active ingredient, about 24%, w/w, of the active ingredient; about 26% w/w of the active ingredient; about 28%, w/w of the active ingredient, about 30%, w/w, of the active ingredient, about 32%, w/w, of the active ingredient; between about 1% and about 10%, w/w of the active ingredient; between about 2% and about 8% w/w of the active ingredient; between about 3% and about 7% w/w of the active ingredient; between about 4% and about 6% w/w of the active ingredient. [0079] Glidants can be added to improve the flow properties of a powder composition or granulate and improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, calcium silicate, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, tribasic calcium phosphate, and talc. Appropriate amounts to use may be determined by those of skill in the art.

Permeation enhancers are an included excipient in one embodiment. Permeation enhancers act to enhance uptake of a substance through the intestinal wall and deliver more of a substance to the bloodstream. Movement through the intestinal wall may occur by passive diffusion, the movement of drug across a membrane in a manner driven solely by the concentration gradient; by carrier-mediated diffusion, movement of drug across a cell membrane via a specialized transport system embedded in the cell membrane; paracellular diffusion, the movement of drug across a membrane by going between, rather than through, two cells; and transcellular diffusion, the movement of a drug across the cell. Additionally, there are numerous cellular proteins capable of preventing intracellular accumulation of drugs by pumping drug that enters the cell back out. These are sometimes called efflux pumps. One of the most important is p-glycoprotein, which is present in many different tissues in the body (e.g., intestine, placental membrane, blood-brain barrier). Permeation enhancers can work by facilitating any of the processes mentioned above (such as by increasing fluidity of membranes, opening "tight junctions" between cells, and/or inhibiting efflux.)

Examples of suitable permeation inhibitors include, for example, but are not limited to, surfactants. Suitable examples for the present invention include are known and commercially available, e.g. from the BASF company under the trade mark SOLUTOL. An example is SOLUTOL HS 15 which is known, e.g. from the BASF technical leaflet MEF 15 IE (1986), to comprise of about 70% polyethoxylated 12-hydroxystearate by weight and about 30% by weight unesterified polyethylene glycol component. SOLUTOL HS 15 has a hydrogenation value of 90 to 110, a saponification value of 53 to 63, an acid number of maximum 1, and a maximum water content of 0.5% by weight. Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers are included in one embodiment, for example of the type known and commercially available under the trade names PLURONIC, EMKALYX and POLOXAMER. A further example of this class is POLOXAMER F127. Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the trade name MIGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth are also included in some embodiments. Other examples include propylene glycol mono C₈ esters include SEFSOL 218 (Nikko Chemicals) and CAPRYOL 90 (Gattefosse) and tocopherol esters, e.g. tocopheryl acetate and tocopheryl acid succinate (HLB of about 16), transesterified ethoxylated vegetable oils are known and are commercially available under the trade name LABRAFIL. Examples are LABRAFIL M 2125 CS (obtained from corn oil and having an acid number of less than about 2, a saponification number of 155 to 175, an HLB value of 3 to 4, and an iodine number of 90 to 110), and LABRAFIL M 1944 CS (obtained from kernel oil and having an acid number of about 2, a saponification number of 145 to 175 and an iodine number of 60 to 90). LABRAFIL M 2130 CS (which is a transesterification product of a C_12-18 glyceride and polyethylene glycol and which has a melting point of about 35 to 4°C. an acid number of less than about 2, a saponification number of 185 to 200 and an iodine number of less than about 3). In one embodiment, the transesterified ethoxylated vegetable oil is LABRAFIL M 2125 CS which can be obtained, for example, from Gattefosse, Saint-Priest Cedex, and France. In one embodiment, a permeation enhancer includes water soluble tocopheryl polyethylene glycol succinic acid esters (TPGS), e.g. with a polymerization number ca 1000, e.g. available from Eastman Fine Chemicals Kingsport, Term., USA. Other embodiments include POLOXAMER compounds, particularly F 127, chitosan, carboxymethylcellulose, SOLUTOL compounds, sodium laurate, and LABRAFIL compounds. Other permeation enhancers include alcohols, dimethyl sulfoxide, glyceryl monooleate, glycofurol, isopropyl myristate, isopropyl palmitate, lanolin, linoleic acid, myristic acid, oleic acid, oleyl alcohol, palmitic acid, polyoxyethylene alkyl ethers, 2-pyrrolidone, sodium lauryl sulfate, and thymol. Appropriate amounts to use can be determined by one of skill in the art.

In some embodiments, the formulation of the present invention, in particular the active ingredient unit comprised therein comprises a release modifying substance. These substances have the function to, e.g. prolong the time required to release the entire active ingredient comprised in the active ingredient unit, once the coating has been removed. Examples of such release modifying substances are biocompatible biodegradable polymers and biocompatible non biodegradable polymers. The proportion of pharmaceutical active ingredient comprised in the active ingredient and the release modifying substance can be varied within wide limits depending on the selected active substance and desired release pattern. The release modifying substance can be, relative to the active ingredient, in the amount of about 1% w/w of the active ingredient, about 2% w/w of the active ingredient; about 3%, w/w/ of the active ingredient; about 4%, w/w of the active ingredient; about 5%, w/w/ of the active ingredient, about 6%, w/w, of the active ingredient, about 7%, w/w, of the active ingredient, about 8%, w/w, of the active ingredient; about 9%, w/w, of the active ingredient; about 10% w/w of the active ingredient t; about 12%, w/w of the active ingredient; about 14%, w/w, of the active ingredient, about 16%, w/w/, of the active ingredient; about 18% w/w of the active ingredient; about 20%, w/w of the active ingredient, about 22%, w/w, of the active ingredient, about 24%, w/w, of the active ingredient; about 26% w/w of the active ingredient; about 28%, w/w of the active ingredient, about 30%, w/w, of the active ingredient, about 32%, w/w, of the active ingredient; about 38%, w/w, of the active ingredient, about 40%, w/w, of the active ingredient; about 42% w/w of the active ingredient; about 44%, w/w of the active ingredient; about 46%, w/w, of the active ingredient, about 48%, w/w/, of the active ingredient; about 50% w/w of the active ingredient; about 52%, w/w of the active ingredient, about 54%, w/w, of the active ingredient, about 56%, w/w, of the active ingredient; about 58% w/w of the active ingredient; about 60%, w/w of the active ingredient, about 62%, w/w, of the active ingredient, about 64%, w/w, of the active ingredient; about 66% w/w of the active ingredient; about 68%, w/w of the active ingredient, about 70%, w/w, of the active ingredient, about 72%, w/w, of the active ingredient; about 74% w/w of the active ingredient; about 76%, w/w of the active ingredient; about 78%, w/w, of the active ingredient, about 80%, w/w/, of the active ingredient; about 82% w/w of the active ingredient; about 84%, w/w of the active ingredient, about 86%, w/w, of the active ingredient, about 88%, w/w, of the active ingredient; about 90% w/w of the active ingredient; about 92%, w/w of the active ingredient, about 91%, w/w, of the active ingredient, about 96%, w/w, of the active ingredient; about 98%, w/w, of the active ingredient, or more, if determined to be appropriate; between about 1% and about 90%, w/w of the active ingredient; between about 10% and about 80% w/w of the active ingredient; between about 30% and about 70% w/w of the active ingredient; between about 40% and about 60% w/w of the active ingredient.

Biocompatible polymers suitable as release modifying agent include biodegradable and nonbiodegradable polymers and blends and copolymers thereof, as described herein. A polymer is biocompatible if the polymer and any degradation products of the polymer are non-toxic to the recipient and also possess no significant deleterious or untoward effects on the recipient's body, such as a significant immunological reaction at the injection site.

Biodegradable polymers usable as release modifying substance are polymers which will degrade, disintegrate or erode in vivo to form smaller chemical species. Degradation can result, for example, by enzymatic, chemical and physical processes. Suitable biocompatible, biodegradable polymers include, for example, poly (lactides), poly (glycolides), poly (lactide- co-glycolides), poly (lactic acid), poly (glycolic acid), polycarbonates, polyesteramides, polyanydrides, poly (amino acids), polyorthoesters, poly (dioxanone), poly (alkylene alkylate), copolymers or polyethylene glycol and polyorthoester, biodegradable polyurethane, blends thereof, and copolymers thereof.

Non-biodegradable polymer usable as release modifying substance are polymers, which will not or essentially not erode in vivo during the biological half-life of such a polymer within the body, i.e. the mean residence time in the body. The mean residence time in the gastrointestinal system is usually between 8 to 48 h, depending on the respective gastrointestinal system. Thus, non-biodegradable polymers will not or essentially not erode during that time period. Preferred examples of biocompatible non-biodegradable polymers include, for example, polyacrylates, polymers of ethylene- vinyl acetates and other acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends thereof, and copolymers thereof.

In a preferred embodiment the formulation of the present invention the active ingredient unit comprises one or more pharmaceuticals, minerals, vitamins and other nutraceuticals, and mixtures thereof. It is particularly preferred that the active ingredient unit comprises one or more pharmaceuticals. In this case the formulation is also referred to as "pharmaceutical formulation" in the remainder of the description.

It is evident that the benefit of the PCS coating is not limited to a particular drug but has utility for almost any drug. Particularly preferred pharmaceuticals are those that can be or are routinely administered via the oral route. In some cases pharmaceuticals, which have not been administered via the oral route due to instability, if exposed to the acidic environment and/or enzymes of the stomach, can be also administered via the oral route, e.g. small peptide drugs, antibodies, or phosphatidyl choline, once the PCS coating is applied. Preferred pharmaceuticals are selected from the group consisting of analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, immunostimulants, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.

Preferably one or more pharmaceuticals are selected from anti-inflammatory agents. These comprise both substances which lower the activity of immune response as well as substances with an anti-inflammatory action, preferred examples are glucocorticoids, in particular beclomethasone, betamethasone, clocortolone, cloprednol, cortisone, dexamethasone. fludrocortisone, fludroxycortide, flumetasone, fluocinolone acetonide, fluocinonide, fluocortolone, fluorometholone, fluprednidene acetate, hydrocortisone, paramethasone, prednisolone, prednisone, prednylidene, pregnenolone, triamcinolone or triamcinolone acetonide, a cyclosporin, in particular cyclosporin A, mycophenolate mofetil, tacrolimus, rapamycin, FK 506, cycloheximide-N-(ethyl ethanoate), azathioprine, ganciclovir, an anti- lymphocyte globulin, ascomycin, myriocin, a pharmacological inhibitor of MAP kinases (especially a p38 inhibitor such as VX-745), caspase inhibitors, matrix metalloproteinase inhibitors, and/or methotrexate.

Preferably one or more pharmaceuticals are selected from substances that have analgesic, anti-inflammatory, and antipyretic effects, preferably non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are drugs with analgesic, antipyretic and, in higher doses, antiinflammatory effects - they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. Preferred NSAIDs are salicylates, in particular acetylsalicylic acid, amoxiprin, benorylate/Benorilate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, and salicylamide; arylalkanoic acids, in particular, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, and tolmetin; 2-arylpropionic acids, in particular ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, or tiaprofenic acid; N-arylanthranilic acids, in particular mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid; pyrazolidine derivatives, in particular phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone; oxicams, in particular piroxicam, droxicam, lornoxicam, meloxicam, or tenoxicam; COX-2 inhibitors, in particular celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, or valdecoxib; sulphonanilides, in particular nimesulide; licofelone; or omega-3 fatty acids. In a preferred embodiment, the pharmaceutic is selected from propionic acid derivative NSAID, e. g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In another embodiment of the invention, the pharmaceutics may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.

"Immunostimulant" encompasses all substances, which influence the function of cells which are involved directly or indirectly in mediation of the immune response, and where the influence leads to an immune response. These cells include, for example, macrophages, Langerhans cells and other dendritic cells, lymphocytes, indeterminate cells, but also cells which do not themselves belong to the immune system but are involved in immune disorders of the skin, such as fibroblasts, keratinocytes and melanocytes, but especially Langerhans cells. The strength of the immune response can be determined for example through the amount of cytokines produced (such as interferon-gamma), detection of activation markers on dendritic cells (such as MHCII or CD86) or the number of activated CD8-positive T cells in the skin. Immunostimulants for the purpose of the present invention are, in particular, plant immunostimulants which are obtained, for example, from Echinacea pallida or Echinacea purpurea, cytokines such as, for example, interleukins, interferons and colony-stimulating factors, and bacterial constituents or molecules which mimic the latter such as bacterial DNA and unmethylated oligodeoxynucleotides with CpG sequences, and constituents of the bacterial cell wall or coat, especially the lipopolysaccharides and molecules derived therefrom, such as monophosphoryl-lipid A, muramyldipeptide (N-acetylmuramyl-L-alanyl- D-isoglutamine), and/or PamCys3, and other molecules such as tetanus toxoid, poly-L- arginine or MHCII peptides.

"Antibiotics" encompasses preferably penicillin's, cephalosporin's, tetracycline's, amino glycosides, macrolide antibiotics, lincosamides, gyrase inhibitors, sulfonamides, trimethoprim, polypeptide antibiotics, nitroimidazole derivatives, amphenicol, in particular actinomycin, alamethicin, alexidine, 6-aminopenicillanic acid, amoxicillin, amphotericin, ampicillin, anisomycin, antiamoebin, antimycin, aphidicolin, azidamfenicol, azidocillin, bacitracin, beclomethasone, benzathine, benzylpenicillin, bleomycin, bleomycin sulfate, calcium ionophore A23187, capreomycin, carbenicillin, cefacetrile, cefaclor, cefamandole nafate, cefazolin, cefalexin, cefaloglycin, cefaloridine, cefalotin, cefapirin, cefazolin, cefoperazone, ceftriaxone, cefuroxime, cephalexin, cephaloglycin, cephalothin, cephapirin, cerulenin, chloramphenicol, chlortetracycline, chloramphenicol diacetate. ciclacillin, clindamycin, chlormadinone acetate, chlorpheniramine, chromomycin A3, cinnarizine, ciprofloxacin, clotrimazole, cloxacillin, colistine methanesulfonate, cycloserine, deacetylanisomycin, demeclocycline, 4,4'-diaminodiphenyl sulfone, diaveridine, dicloxacillin, dihydrostreptomycin, dipyridamole, doxorubicin, doxycycline, epicillin, erythromycin, erythromycin stolate, erythromycin ethyl succinate, erythromycin stearate, ethambutol, flucloxacillin, fluocinolone acetonide, 5-fIuorocytosine, filipin, formycin, fumaramidomycin, furaltadone, fusidic acid, geneticin, gentamycin, gentamycin sulfate, gliotoxin, gramicidin, griseofulvin, helvolic acid, hemolysin, hetacillin, kasugamycin, kanamycin (A), lasalocid, lincomycin, magnesidin, melphalan, metacycline, meticillin, mevinolin, micamycin, mithramycin, mithramycin A, mithramycin complex, mitomycin, minocycline, mycophenolic acid, myxothiazole, natamycin, nafcillin, neomycin, neomycin sulfate, 5-nitro-2-furaldehyde semicarbazone, novobiocin, nystatin, oleandomycin, oleandomycin phosphate, oxacihin, oxytetracycline, paromomycin, penicillin, pecilocin, pheneticillin, phenoxymethylpenicillin, phenyl aminosalicylate, phleomycin, pivampicillin, polymyxin B, propicillin, puromycin, puromycin aminonucleoside, puromycin aminonucleoside 5'-monophosphate, pyridinol carbamate, rolitetracycline, rifampicin, rifamycin B, rifamycin SV, spectinomycin, spiramycin, streptomycin, streptomycin sulfate, sulfabenzamide, sulfadimethoxine, sulfamethizole, sulfamethoxazole, tetracycline, thiamphenicol, tobramycin, troleandomycin, tunicamycin, tunicamycin Al homolog, tunicamycin A2 homolog, valinomycin, vancomycin, vinomycin Al, virginiamycin Ml, viomycin and/or xylostasin.

"Antiinfectives" encompasses preferably antimycotics, agents with antiparasitic effect and virustatics, in particular amphotericin, vifonazole, buclosamide, quinoline sulfate, chlormidazole, chlorphenesin, chlorquinaldol, clodantoin, cloxiquine, cyclopirox olamine, dequalinium chloride, dimazole, fenticlor, flucytosine, griseofulvin, ketoconazole, miconazole, natamycin, sulbentine, tioconazole, toinaftate, antiretroviral agents and/or herpes remedies.

"Antiallergics" encompasse preferably substances from the class of globulins, corticoids or antihistamines, in particular beclomethasone and derivatives thereof, betamethasone cortisone and derivatives thereof, dexamethasone and derivatives thereof, bamipine acetate, buclizine, clemastine, clemizole, cromoglicic acid, cyproheptadine, diflucoitolone valerate, dimetotiazine, diphenhydramine, diphenylpyraline, ephedrine, fluocinolone, histapyrrodine, isothipendyl, methdilazine, oxomemazine, paramethasone, prednylidene_., theophylline, and/or tolpropamine tritoqualine. Many labile peptide and protein drugs are amenable to being coated with PCS. In a preferred embodiment a powder, micropellets or granules of the peptide or protein drug is coated. Preferred polypeptides and proteins are preferably selected from the group consisting of erythropoietin, oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-α., -β or -γ, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage- colony stimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-I), interleukin-11 (IL-I l), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins and synthetic analogues, modifications and pharmacologically active fragments thereof, enzymes, cytokines, antibodies and vaccines, in particular insulin. The term antibodies also comprises single chain antibodies, Fc-fragments, Fab-fragments and other art know variations of antigen binding proteins.

The only limitation to the polypeptide or protein drug which may be utilized is one of functionality, e.g. the ability to cross the colon wall, which may be required to exert its function, unless the proteins exerts its effects at least in part directly in the colon or by interacting with the colon wall. In some instances, the functionality or physical stability of polypeptides and proteins can also be increased by addition of various additives. Suitable additives, such as polyols (including sugars), amino acids, surfactants, polymers, other proteins and certain salts may be used. These additives can be readily incorporated into the active ingredient unit comprised in the formulation of the present invention.

As indicated above the formulations of the present invention are intended for oral delivery. Oral delivery includes formats such as tablets, capsules, caplets, and/or suspensions and may also comprise a plurality of granules, beads, powders or pellets. Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and are described in the pertinent texts, e.g., in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 20th Edition, Lippincott Williams & Wilkins, 2000). In a preferred embodiment the PCS coating is applied directly onto the surface of an administration form, e.g. onto tablets, caplets, pills, hard or soft capsules, sachets, micro-pills or mini-tablets to provide the benefits of the present invention. In this case the active ingredient unit itself is a tablet, a caplet, a pill, a hard or soft capsule, a micro-pill or a mini- tablet. In most cases of this embodiment the formulation will only comprise one active ingredient unit. This embodiment is particularly suitable to improve commercially available administration forms of pharmaceuticals.

In a further preferred embodiment the active ingredient units are selected from granules, beads, micro beads, pellets, micro pellets and powders. Granules are small particles gathered into larger, permanent aggregates in which the original particles can still be identified. Granules can be generated from micro-pellets, powders and micro-beads by art known processes including, e.g. fluidized bed granulation. Pellets and micropellets are formed by pelletizing, which is a process of compressing or molding of a product into preferably spherical shape. Pellets and micropellets are distinguished by their grain size. Pellets within the meaning of the present invention have a grain size of above 1 mm and preferably below 5 mm and micro pellets have a grain size of less than 1 mm and more than 10 μm. Beads and micro beads are distinguished from pellets and micro pellets, respectively, by their spherical shape, i.e. the grain size equates diameter. Thus, beads within the meaning of the present invention have a diameter of above 1 mm and preferably below 5 mm and micro beads have a diameter size of less than 1 mm and more than 10 μm. Powders have a grain size of less then 10 μm and preferably more than 0.1 μm, preferably more than 0.5, 1, 2, 3, 4, or 5 μm. If the active ingredient unit is small, e.g. a grain size of 5 mm or less it is preferred that the formulation of the present invention comprises more than one active ingredient unit. In the case of granules, beads, pellets and micropellets the formulation of the present invention, preferably comprises between 10 and 100.000, preferably 20 to 10.000 active ingredient units. The active ingredient units, can be individually coated or can be clustered together to form coated granules, e.g. if the PCS is applied to active ingredient pellets, micropellets or beads in a granulation or fluidized granulation process. An appropriate number of active ingredient units to provide the desired unit dosage may then be formulated into tablets, caplets, pills, hard or soft capsules, syrups, suspensions, lozenges, sachets, or pastilles. In case of liquid formulations like syrups or suspensions it is preferred that the liquid formulation has an acidic pH, preferably below pH 4.0, which may be attained by suitable pharmaceutically acceptable acids, e.g. hydrochloric acid or citric acid. The acidity in the liquid formulation prevents dissolution of the PCS coating surrounding the active ingredient units, which will be stable under these conditions. Tablets may be formed from such coated active ingredient units by art known tabletting processes described in more detail below.

If the active ingredient unit is a powder, it is preferred that the powder is PCS coated by embedding the powder grains in the coating material. Thus, it is preferred that a slurry of the coating material and the powder is generated by mixing. The slurry may then be formed into a suitable formulation form, e.g. a tablet, a caplet or a pill. It is particularly preferred that protein and peptide powders, in particular insulin are formulated in this way.

Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed. Tablets are used in one embodiment. Tablets may be manufactured using standard tablet processing procedures and equipment. One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active ingredient in uncoated form or the active ingredient unit in coated form, alone or in combination with one or more excipient or release modifying substance. As an alternative to direct compression, tablets can be prepared using wet- granulation or dry- granulation processes. Tablets may also be molded rather than compressed, starting with a moist or otherwise tractable material; particularly, compression and granulation techniques are used in one embodiment.

In another embodiment, capsules may be used. Soft gelatin capsules may be prepared in which capsules contain a mixture of the active ingredient in uncoated form or the active ingredient unit in coated form and vegetable oil or nonaqueous, water miscible materials such as, for example, polyethylene glycol and the like. Hard gelatin capsules may contain granules of the active ingredient in uncoated form or the active ingredient unit in coated form in combination with a solid, pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. A hard gelatin capsule shell can be prepared from a capsule composition comprising gelatin and a small amount of plasticizer such as glycerol. As an alternative to gelatin, the capsule shell may be made of a carbohydrate material. The capsule composition may additionally include colorings, flavorings and opacifiers as required. In a preferred embodiment of the formulation of the present invention the PCS is the product of a hydrolysis condensation reaction (HCR) of a cyclic carbohydrateoxysiloxanol of the general formula: Si_nO_n(OH)_x(OR)_2n-X is formed wherein n is 3, 4 or 5 and x is 1, 2 or 3; wherein R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted. A preferred value for n is 4 and x = 0, other preferred values are n = 4 and x = 1 ; n=5 and x = 1 ; n = 3 and x = 2. It is preferred that only one type of carbohydrateoxysiloxanol is used in the reaction. It is further preferred that all R residues of the cyclic carbohydrateoxysiloxanol are identical. When the formulation of the present invention reaches, e.g. the aqueous, acidic environment of the stomach all outer remaining O-R residues will be hydrolyzed and the respective R-OH compounds are released. The inner O-R groups stay as long as the PCS is not completely removed from the surface of the active substance coated. It is, therefore, preferred that the released alcohols exhibits a low toxicity in animals and humans, in particular in human patients. The skilled person would know how to select an appropriate PCS providing no toxicity at the concentration of a unit dose of the respective active ingredient and, which are, thus, pharmaceutically acceptable.

It is preferred that the alkyl residue is selected from C₂ to Ci₀ alkyl, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or C]₀, optionally substituted. A preferred substituent is F. It is particularly preferred that the alkyl is ethyl, 1 -propyl, 2-propyl, glyceryl, 1 -butyl, 2-butyl, tert-butyl or mixtures thereof. More preferred is ethyl, 1 -proyp, or 2-propyl and most preferred ethyl, since the use of ethyl will lead to the release of the non toxic alcohol ethanol. Such preferred cyclic carbohydratesiloxane are formed by using, e.g. tetraethoxysilan (TEOS)₃ or tetrapropoxysilan, as the starting siloxan compound as described in greater detail below.

It is preferred that the alkenyl residue is selected from C₂ to Cjo alkenyl, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or C₁₀, optionally substituted. A preferred substituent is F.

It is preferred that the alkoxy residue is selected from C₂ to C₁₀ alkoxy, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or Cio, optionally substituted. A preferred substituent is F.

The carbohydrate oxysiloxanols of the general formula: Si_nO_n(OH)_x(OR)_2n-X undergo further hydrolysis condensation reactions to form quasi cubic structures like tricyclic alkoxysiloxanol comprising Si_nO_n+2(OH)_x(OR)_2n-4._x wherein n is 6, 7, 8 and x is 1, or 2. These can further react to form incompletey condensed oligosilesquioxanes in the form of chains of cube like struktures, which may have lengths of 100 nm to 10,000 run and more, preferably 100 to 1,000 nm length. The diagonal of the cubes or quasi cubes are about 0.8 nm. Thus, to provide the desired structural viscosity it is preferred that between at least 100 to about 10.000, preferably between 1,000 to about 5,000 cubes, quasi cubes or mixtures thereof are linked to one chain. The cubic chains interact with each other via hydrogen bonds. Macroscopically the mono-dimensional chain structure is reflected by a special viscosity called "structural viscosity". The extent of chain formation is kinetically controlled and/or by residual alcohol, TEOS or dimeric siloxane content in the oligosilesquioxanes sol that is formed. The term "maturated PCS" refers to chains of incompletely condensed oligosilesquioxanes, which have formed after the maturation by HCR is terminated. A maturated PCS is incompletely condensed, if less than 10%, preferably less than 5%, less than 1%, less than 0.5% of the organic residues remain available for condensation reactions. Preferably; the individual quasi cubes have in the chains have a general unit structure of -[-OSi_nCv₂(OR)_n+1-]- wherin n is 6, 7, 8.

As outlined above the PCS coating primarily serves the purpose of protecting the active ingredient to be administered from being released in the acidic environment of the stomach. Thus, the coating has to be fluid tight, i.e. it does not exhibit any holes or gaps. To that end a sufficient amount of coating material has to be applied that forms a closed layer around the active ingredient unit, hi a preferred embodiment of the formulation of the present invention the coating surrounding the active ingredient unit has a thickness of between 1 μm to 2 mm, preferably between 10 μm to 1 mm, more preferably 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, or 900 μm. The respectively required thickness will also depend on the grain size of the active ingredient unit. If a tablet or capsule is coated, then the coat will generally be thicker than if small grain size micro bead, micro pellets or granules are coated. The thickness of the coating will also influence the release pattern. The thicker the coating the longer the time required and/or the higher the pH has to rise in order to allow complete dissolution of the coating and subsequently release of the active ingredient. When the coating has a thickness above 200 μm it will withstand pHs of up to 8.0 for at least 10 mins, before a significant release, e.g. more than 10% of the active ingredient occurs. This pH is significantly higher than the nH of about 6.8 which leads to the degradation of art known enteric coatings. Depending on the desired active ingredient release pattern the active ingredient unit comprised in the formulation of the present invention comprises one or more coatings beneath and/or on top of the PCS coating. It is preferred that an enteric coating is on top of the PCS coating, i.e. that any fluid contacting the formulation of the present invention first makes contact, with this coating before making contact with the PCS coating.

Thus, one or more coating layers, preferably enteric coating layers are applied onto the active ingredient unit or onto the active ingredient unit covered with separating layer(s) by and/or covered with a PCS coating using a suitable coating technique. Preferably the enteric coating layer is applied to (an) active ingredient unit(s), which is(are) already coated with PCS. The enteric coating material may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating layer polymers one or more, separately or in combination, of the following can be used, e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymer(s).

The enteric coating layers may contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

The amount of plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer(s), selected plasticizer(s) and the applied amount of said polymer(s), in such a way that the mechanical properties, i.e. flexibility and hardness of the enteric coating layer(s), for instance exemplified as Vickers hardness, are adjusted so that the acid resistance of the pellets covered with enteric coating layer(s) does not decrease significantly during compression of pellets into tablets. The amount of plasticizer is usually above 10% by weight of the enteric coating layer polymer(s), preferably 15-50% and more preferably 20-50%. Additives such as dispersants, colorants, pigments polymers e.g. poly (ethylacrylat, methylmethacrylat), anti-tacking and anti-foaming agents may also be included into the enteric coating layer(s). Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible material. In a preferred embodiment of the formulation of the present invention the enteric coating comprises, essentially consists or consists of hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phthalate, hydroxylmethylcellulose phthalate, hydroxymethylmethylcellulose acetate succinate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate trimellitate, and mixtures thereof.

Preferably the methacrylic acid copolymer is selected from the group consisting of a cationic copolymer of dimethyl aminoethyl methacrylate and neutral methacrylic esters, trimethylaminoethylmethacrylate and neutral methacrylic esters, and anionic polymers of methacrylic acid and methacrylates with carboxyl functional groups.

(a) carrying out a first HCR of one residue X of one or more identical or different, preferably identical Si-compounds of the following formula (I) SiX_mYn

(I) wherein X is the same or different and selected from hydroxyl or -OR, optionally substituted, Y is hydrogen, m is 2, 3, or 4, n is 0, 1, or 2 and m + n = 4 in a water comprising solvent; (b) carrying out a second HCR, wherein the material obtained in step (a) is reacted while removing the solvent until a cyclo RO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-X is formed wherein n is 3, 4 or 5 and x is 1, 2 or 3; and (c) carrying out at least a third HCR, wherein the material obtained in step (b) is reacted to obtain a maturated PCS, wherein R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl. In the general formula I the terms alkyl, alkenyl, alkoxy and acryl have the above indicated preferred and particularly preferred meanings. In preferred Si-compounds according to formula (I) R has the same meaning for all X.

Preferably, the alkyl residue is selected from C₂ to Cio alkyl, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or Cio, optionally substituted. A preferred substituent is F. It is preferred that the alkyl is ethyl, 1 -propyl, 2-propyl, glyceryl, 1 -butyl, 2-butyl, tert-butyl or mixtures thereof. More preferred is ethyl, 1-proyp, or 2-propyl and most preferred ethyl, since the use of ethyl will lead to the release of the non toxic alcohol ethanol. Such cycloalkoxysiloxanol are formed by using, e.g. tetraethoxysilan (TEOS) as the starting silan compound as described in greater detail below. It is preferred that the alkenyl residue is selected from C₂ to Ci₀ alkenyl, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or C₁₀, optionally substituted. A preferred substituent is F. It is preferred that the alkoxy residue is selected from C₂ to Ci₀ alkoxy, i.e. C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉ or Ci₀, optionally substituted. A preferred substituent is F. It is preferred that the SiX₀₁Y_n compounds employed in one reaction (a) are identical.

The structure of the condensation products formed in the first and each subsequent HCR will depend on the ratio of the molar equivalents (R- factor) of water to Si-compound(s) of formula (I). The higher the water content the more rapid and extensive the condensation reaction. If a large excess of water is supplied all carbohydrate residues will hydrolyze and extended three- dimensional hydrophilic silanol structures will form that are not suitable as coating. Thus to ascertain that only one X is reacted at least partly preferentially completely in the first HCR of step (a) and that primarily dimers are formed the R-factor is preferably between 0.5 to 2.0, i.e. 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0; preferably between 0.6 to 1.9, more preferably between 0.7 to 1.0. The molar equivalents of water in the reaction for purpose of calculating the R-factor consist of any water that is specifically added to the solvent and any water that may be added as part of other reagents, in particular as part of the acid. It is preferred that the first HCR of step (a) leads to the formation of at least 80% dimers of the Si-compound(s) of formula (I), preferably 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%.

In a preferred embodiment of the method of the present invention the reaction of step (a) is catalyzed by acid addition and at an initial pH of < 7. Thus, for step (a) preferably an initial pH of between 0 to < 7, preferably of 2 to 3.5 is used. The pH is preferably adjusted by an acid like, e.g. diluted nitric acid. Diluted nitric acid at a concentration of 1 N to 0.01 N is preferred. Suitable are all acidic mixtures and solutions that are capable of locally producing NO or NO₂. These can be acidic mixtures and solutions, which react enzymatically with, e.g. molecular oxygen to generate NO. Suitable enzymes are well known to the skilled person and comprise, e.g. nitric oxide synthetase (NOS). The enzymatic release of NO requires the presence of thiolgroups (SH) as are present in cysteins. Thus, in a preferred embodiment of the method of the present invention pH of less than pH 7 in step (a) is obtained with diluted nitric acid or (b) solutions or mixtures of (i) a physiologically acceptable organic acid and (ii) a substrate for nitric oxide synthetase (NOS).

Alternatively to the use of nitric acid an aqueous and/or alcoholic solution of a physiologically acceptable acid may be used, e.g. citric acid, malic acid, succinic acid, tartaric acid, or ascorbic acid, which further comprise at least one amino acid, preferably an essential amino acid, e.g. L-arginine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-methionine, L-tyrosine, L-lycine, L-tryptophane or a non-essential amino acid, e.g. L-glutamine, L- asparagine, L-glutamic acid, L-asparagic acid, L-cysteine, L-glycine, L-alanine, L-proline, L- histidine, and L-tyrosine, which is suitable as substrate for NOS. Preferably the alcohol is the same or has a similar boiling point as the alcohol released during the HCR. A particularly preferred solution for carrying out step (a) is, thus, an aqueous diluted ethanolic solution comprising an amino acid and NOS.

In cases wherein nitric acid is used to adjust the pH, it is preferred that the diluted nitric acid is used in a molar relation to the SiX_mY_n of Si-compound/nitric acid in the range of 110:1 to 90:1. In a particularly preferred embodiment a ratio of TEOS/HNO₃ of 100:1 is used.

The preferred solvent comprising water for carrying out step (a) is an alcohol:water mixture, which is capable of solubilizing the SiX_mY_n compound. Preferred alcohols are alcohols that are also released during the HCR reaction or those that have a least a similar boiling point. A particularly preferred alcohol for carrying out this step is ethanol. Thus, a preferred reaction mixture will comprise between 0.8 to 2.0 mol alcohol for each mol SiX_n, Y_n compound, preferably TEOS. More preferably the relation is 1 to 1.5 mol alcohol for each mol SiX_n, Y_n compound, preferably TEOS. Accordingly, in a preferred embodiment, 0.6 to 1.9 Mol H₂O and 0.001 to 0.01 Mol HNO₃ and 1 to 1.5 Mol alcohol, and 1 Mol TEOS are used. A particularly preferred reaction according to step (a) of the present invention will comprise the following components in the respectively indicated ratios: 1 MoI SiX_1nY_n compound, preferably TEOS mixed with 1.26 MoI alcohol, preferably ethanol. This mixture is stirred until the SiX_1nY_n compound is dissolved or at least homogenously resuspended. 10 g 1 N HNO₃ (corresponding to 0.63 g HNO₃) are diluted in 23 g H₂O. The molar ratio of HNO₃/to H₂O is about 0.01/1.80. The diluted nitric acid is added to the alcoholic solution.

The first HCR proceeds exothermically in a way that one RO-group of a SiX₀₁Y_n, preferably a EtO-group, dimerizes with another SiX₀₁Y_n compound and releases one alcohol molecule, preferably ethanol molecule and water. Preferably the two solutions, namely alcohol/ SiX₀₁Y_n- compound and diluted nitric acid, are combined under stirring at about room temperature. The temperature rises during the dimerization to about 50 to 60⁰C. The starting temperature is not critical since the temperature will inevitably rise, in as long as it is high enough that the first HCR can occur. Thus, the starting temperature is preferably between 10 to 70°C. For economical reasons a starting temperature at RT is preferred. As the speed of the first HCR is influenced by the reaction temperature lower temperatures will result in longer reaction times and higher temperatures in shorter reaction times. In a preferred embodiment the reaction will be carried out between 1 to 12 h, preferably for 5 to 8 h. After this time and under the indicated conditions the thermodynamically stable dimer will be preferentially formed.

Once the first HCR is completed the sol is preferably stirred until it has cooled down to RT. It is preferred that step (b) immediately follows step (a) and that the stirring is not interrupted for prolonged periods of time.

Step (b) is carried out with the siloxanol material obtained in step (a) in a closed, preferably gastight reactor. For small scale production this reactor may be a rotary evaporator or for larger scale production a tank, which is provided with a means to lower the gas pressure, a heating means and/or a reflux or distillation column. The reaction of step (b) is preferably carried out at reduced gas pressure and/or elevated temperature. The reduced pressure and/or elevated temperature are preferably chosen in such to provide evaporation of the solvent including the alcohol, in particular ethanol, and traces of water formed during side condensation reactions in step (a) and (b) as well as the acid. Thus, in a preferred embodiment step (b) is carried out at between 10 to 1013 mbar, preferably at between 100 to 800 mbar. Suitable temperatures are in the range of 10 to 100°C preferably 60⁰C to 7O⁰C. The skilled person is capable of selecting the appropriate pressure and temperature to effect the desired evaporation of solvent, water, acid and/or alcohol. When selecting the appropriate temperature care should be taken not to exceed the boiling point of the respective alcohol, e.g. 78°C for ethanol, to prevent bubbling and possibly foaming of the solution. When ethanol is used as the solvent and ethanol is also generated in the hydrolysis reaction it is, thus, preferred that the temperature is between 60 to 78°C. Temperatures above 60°C are also advantageous, if HNO₃ is used as NO donor, since in this case temperatures above 6O⁰C facilitate the evaporation of NO₂ from the reaction vessel, which is advantageous since it lowers the acidity in subsequent HCRs.

It is preferred that no additional water is added to the reaction in step (b) or enters the reaction vessel in the form of humidity, i.e. the R-ratio is not increased. It is understood that the reaction will nevertheless comprise the water initially added in step (a) and the water formed during side condensation reactions in steps (a) and (b).

The "reactive evaporation" step (b) is preferably carried out until the mass loss come to zero and the mass of the reaction product no longer appears to change. These observations are indicative of the formation of cyclo carbohydrateoxysiloxanols of the general formula: Si_nO_n(OH)_x(OR)_2n-X, wherein n is 3, 4 or 5 and x is 1, 2 or 3 and R has the above indicated meanings. As indicated above, it is desirable to decrease the acidity of the solution during step (b), preferably by removing NO₂ from the reaction solution or by adding base. Thus, it is preferred that the evaporation is carried out in a way that the proton concentration is reduced to less than 100 ppm, preferably less than 90 ppm, 80 ppm, 70 ppm, 60 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm or less than 1 ppm. The skilled person will be capable to determine the completion of step (b) by measuring the weight loss until it comes to almost zero, i.e. less than 1.0 %, preferably less than 0.5 % more preferably, less than 0.3 % in 30 min.

It is preferred that the reaction of step (b) is terminated by lowering the temperature, preferably below 10°C. From analysis of the resulting cyclo carbohydratesiloxanols it appears that the warm sol has a composition of Si_nO_n(OH)_x(OR)_2n._x wherein n is 3, 4 or 5 and x is 1, 2 or 3, preferably wherein n is 4 and x is 1.

The reaction conditions of step (b) ascertain that reaction products (e.g. traces of water and alcohol) and NO₂, of HNO₃ is used, which are undesirable in the final product are removed, since it will be difficult to remove these reaction products from the reaction in subsequent HCRs. The resulting structure of the cyclo carbohydratesiloxanols is reflected by the weight loss of the reaction material during the evaporation step, since this depends both on the amount of alcohol formed during the condensation reaction and the alcohol added as a educt in step a. If, e.g. 1.26 mol alcohol per mol TEOS were added in step a, it is preferred that the weight loss, i.e. the alcohol that can be evaporated is in the range of 35 % up to 65 %, preferred in the range of 40 % to 55 %

Step (c) is the kinetically controlled maturation of the cyclotetrasiloxane produced in step (b). This step involves a third HCR, wherein the viscosity of the reaction material is further increased through the formation of incompletely condensed silsesquioxanes of cubic shape or almost cubic shape as outlined above. Preferably these compounds are of the general formula Si_nOn₊₂(OH)χ(OR)_2n-4-χ wherein n is 6, 7, 8 and x is 1, or 2. These incompletely condensed silsesquioxanes react further to form chains of cubes, i.e. oligosilesquioxanes have a general unit structure of -[-OSi_nO_n+2(OR)_n+i-]- wherein n is 6, 7 or 8. This step is preferably also carried out in a closed reaction vessel. The access of gases, in particular of CO₂ should be prevented. Preferably, maturation is carried out at reduced temperature, preferably at a temperature of between -20 to +10⁰C, i.e. at -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10⁰C. The maturation is preferably carried out for a time of 1 day to 4 weeks. Particularly, preferred maturations times are from 2 to 10 days or 3 to 5 day at a temperature of 2 to 10⁰C, preferably 4°C until the desired viscosity is obtained. Preferably the maturated PCS (mPCS) material is coated to the active ingredient unit at a viscosity of less than 70 Pa ^• s. It is preferred in the method of the present invention the viscosity of the material applied during step (d) is below 10 Pa ^• s, preferably below 5 Pa • s, preferably at 4°C. A viscosity below 10 Pa ^• s is particularly preferred; if the coating material is applied to the surface of the active ingredient unit by processes involving spraying of the coating material, e.g. fluidized bed granulation.

In a preferred embodiment of the method of the present invention m = 4, i.e. all substituents of the educt are -OR and even more preferably all R are the same. It is further preferred that R is C₂ to Cio alkyl, optionally substituted, preferably by F, in particular ethyl, 1 -propyl, 2- propyl or butyl. Thus, particular preferred compounds according to formula (I) are tetraethoxysilan (TEOS) or tetrapropoxysilan. In a further aspect the present invention relates to a PCS coating producible by the method of the present invention. In particular preferred embodiments this PCS coatings comprise cyclo carbohydratesilanols.

In a further aspect the present invention relates to a method for producing a formulation comprising one or more active ingredient units comprising the steps of the method of producing a PCS coating further comprising step:

(d) applying the material obtained at the end of step (b) of the method of producing a PCS coating or the material formed during step (c) of the method of producing a PCS coating to the surface of an active ingredient unit.

The term "active ingredient unit" has the same meaning in this context as already outlined above. In a preferred embodiment of this method the material obtained in step (b) is cooled down to a temperature below +10°C after step (b) and prior to step (c). This cooling step is preferably characterized in that the warm microemulsion, which is the product of step (b) is rapidly, i.e. within a few minutes to a few hours, preferably within 10 to 40 mins, cooled down to the temperature that is also used in subsequent step (c). If step (b) has not already been carried out in a gastight reaction vessel, the reaction material is transferred to a gastight reaction vessel. To avoid unwanted side reactions care has to be taken to prevent entry of water even in the form of humidity into the reaction vessel.

As indicated above the pH of the reaction material changes during step (b) due to evaporation of NO₂ or may be adjusted by the addition of base. The pH of the coating material may be further adjusted, preferably to a pH of between 5 to 7, preferably about pH 6 after completion of step (b).

In a further aspect of the method for producing a formulation comprising one or more active ingredient units the method comprises the steps:

(a) providing cyclo RO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-x, wherein n is 3, 4 or 5 and x is 1, 2 or 3 and R is selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted or a matured PCS derived therefrom by at least one further HCR and (b) applying the material to the surface of an active ingredient unit.

In this method R, n, x, alkyl, alkenyl, alkoxy, acryl and "active ingredient unit" have the preferred and particularly preferred meanings indicated above. In the method according to this aspect it is preferred that at least one further HCR is carried out, if a cyclo RO-siloxanol is provided in step (a).

In a preferred embodiment of both methods for producing a formulation the active ingredient unit is selected from the group consisting of tablets, caplets, pills, hard or soft capsules, micro-beads, micro-pills, granules, beads, pellets, micropellets, powders and mini-tablets. In particular, if the active ingredient unit is selected from micro-beads, micro-pills, granules, beads, pellets, and micropellets. These active ingredient units may be used directly without any further formulation or may be formed into the final formulation, e.g. tablets or pills or may be filled into capsules by art known processes. It has been observed that also powders can be coated by this method, which will dissipate into coated powder particles once the coating process is completed.

In a preferred embodiment of the method of the present invention the material of step (b) or

(c) or the provided material is applied to the active ingredient unit by fluidized bed granulation, spray drying or dip coating. The higher the viscosity the more difficult dip coating process will become. Thus, coating material of higher viscosities is preferably used for spray coating and coating material of lower viscosity preferably for dip coating or if powders, micropellets or microbeads are directly stirred into the coating material to form a PCS active ingredient unit slurry, which may then be formed into any suitable administration form. Such slurries may be formed even at high viscosities. Thus, in a preferred embodiment of the method of the present invention the material applied to the active ingredient unit has a viscosity between 1 to 70 Pa ^• s at 4°C, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Pa ^• s at 4°C. Once applied the HCR further proceeds unless the formulation is cooled to about -20°C.

In a further aspect the present invention relates to a formulation producible by a method of the present invention. In a further aspect the present invention relates to a formulation of the present invention for medical use, in particular for oral administration of active ingredients, in particular pharmaceutically active compounds.

In a further aspect the present invention relates to the use of a PCS coating, preferably the PCS coating described above, to protect active ingredient units from degradation or dissolution in acidic environment. Thus, this aspect relates to the use of PCS as an improved enteric coating. In this aspect of the invention PCS is preferably used to replace enteric coatings in commercially available formulations. The term PCS in this context preferably has the preferred and particularly preferred meanings outlined above.

Brief Description of the Tables and Figures

Fig. 1: Panel A depicts the pH dependent dissolution and gelling behaviour of silica gel. Panel B depicts the weight loss under reactive evaporation during step (b).

Fig. 2: Panel A depicts the dissolution behaviour of a PCS coated Diclofenac tablet in solution 1 after 2 h. Panel B depicts the dissolution behaviour of the same PCS coated

Diclofenac tablet in solution 2 (pH 6.8) after 1 h.

Fig. 3: Depicts the amount of Diclofenac detectable in solution 1 (pH 2) or solution 2 (pH

6.8) at different time points over a 3 h period.

Fig. 4: Shell model of PCS disintegration at pH 2 (Panel A) under these conditions no diffusion or synereses due to isoelectrical point IEP occurs and pH 6.8 (Panel B). Examples

Example 1: Synthesis of PCS

The method for producing a formulation comprising PCS coated Bovine Serum Albumine (BSA; Sigma Aldrich No. A2153) comprised the following steps (a) to (c) for the production of maturated PCS and step (d) for the coating of BSA.

In step (a) the first hydrolysis condensation reaction (HCR) was carried out by weighing of 564.91 g (2.7 mol) tetraethoxysilan into a one neck glass flask with a content of about 2 1. To this 156.54 g (3.4 mol) ethanol were added. The solution was stirred with a magnetic stirrer

(MR Hei-Tec from Heidolph) for 30 min untill a clear solution was obtained. In a separate glass flask 33.30 g of 1 molar nitric acid was diluted with 86.49 g water and 33.97 g of this aqueous nitric acid were added to the TEO /ethanol mixture. An exothermic reaction took place. The solution heated up to approximately 60 °C. The reactants were stirred for 18 h while the solution cooled down to room temperature.

In step (b) the second HCR was carried out and a cyclic carbohydratesiloxane was formed by removing the solvent by a rotary evaporator (Laborota 4001 von Heidolph). The glass flask with the solvent was heated in a water bath up to 75 °C. The vacuum pump (Laboxact von KNF LAB, Laboport) was turned on and the valve to the recipient was opened slowly. The pressure was reduced to 500 mbar. The weight loss pattern depicted in Fig. IB shows a parabola. The residual weight loss converges towards 44 %.

In step (c) the third HCR was carried out and the cyclic carbohydratesiloxane was maturated by cooling the cyclic carbohydratesiloxane formed to room temperature and pouring into a closed flaks. The flask with the solvent was set in a refrigerator at 4 ⁰C. The cyclic carbohydratesiloxane was held for 15 days at 4 °C. During that time period the viscosity increases to approx. 1 Pa s. The maturated PCS was formed.

In step (d) BSA was coated by stirring 1 g BSA for 1 hour in 10 g maturated PCS. The resulting suspension was injected into a gelatine caps. The cans were held at room temperature for 2 days. After that time the suspension had geled to a monolith. Example 2: Dispersion and Dissolution of a Polyethoxysiloxane coated Insulin

Insulin powder with a diameter of approx. 3 μm taken from Exubera^® (Pfizer) was coated with Polyethoxysiloxane. Exubera consists of regular human insulin, which exists as a hexamer, a complex of six associated insulin molecules. In order to exert a pharmacological effect, the hexamer must first dissociate into three dimers — complexes of two insulin molecules — which then further dissociate into individual insulin molecules, or monomers. Certain drugs, such as insulin, can be loaded onto these particles by combining mildly acidic solutions of the drug and FDKP (fumaryl diketopiperazine) to form a mixture, which is then dried to form a powder. Diketopiperazines are a class of cyclic organic compounds that result from peptide bonds between two amino acids to form a lactam. They are the smallest possible cyclic peptides.

Polyethoxysiloxane was formed by a synthesis as described. 1 mol TEOS, 1.26 mol ethanol and 0.7 mol water and 0.004 mol HNO₃ was mixed as described in step 1. The mixture was stirred for 12 h. In step 2 the solvent was removed by evacuating down to 20 mbar at 70°C. The residual weight loss was 43 %. The Cyclic alkoxysiloxanol formed was cooled to room temperature and matured for 10 days at room temperature. After 10 days, the polyethoxysiloxane shows an increase in viscosity up to 1 Pa s. The above described Insulin containing powder was thereafter dispersed in polyethoxysiloxane, giving a clear, solvent free dispersion. The alkoxy group of the siloxanol adhered in an excellent manner onto the carboxyl groups of the diketopiperazine. After coating HPLC measurements show stable hexamers of insulin molecules. Neither interaction nor dissolution was observed. The coated powder was dissolved in Pharmacopeia solution 1 and solution 2. After 1 h of dissolution in solution 2 the insulin powder started to disintegrate.

Example 3: Dissolution of a polyethoxysiloxane coated tablet in Pharmacopeia solution 1 and solution 2

Tablets of a non-steroidal anti-inflammatory drug (NSAIDs) e.g. Ketoprofen or Voltaren^® (Novartis) was coated with Polyethoxysiloxane by taking ketoprofen (Spondylon) (i?5)-2-(3- Benzoylphenyl)-Propionic Acid, Diclofenac 2-[2-[(2,6Dichlorphenyl)amino]phenyl]-acetic acid in tablet form. Polyethoxysiloxane was formed by a synthesis as described. 1 mol TEOS, 1.26 mol ethanol and 1.6 mol water and 0.001 mol HNO^ was mixed as step 1 and stirred for 24 h. In step 2 the solvent was removed by evacuating down to 12 mbar at 60°C. The residual weight loss was 52%. The Cyclotetrasiloxan formed was cooled to room temperature and matured for one day at 7°C. Thereafter the polyethoxysiloxane was matured for 12 days until a viscosity of 10 Pa ^• s was reached. The residual matured polyethoxysiloxane was dissolved with DMSO (10 %) to lower viscosity. Before coating the tablets, ethanol was given to the solution. The ethanol/solvent ration was 1/2. This solution was sprayed to the NSAIDs tablets. After spraying the tablets were kept for one day in a closed container with an ethanol atmosphere.

The as coated tablets were dissoluted in Pharmacopeia solution 1 and solution 2. After 2 h dissolution in solution 1 (0.2 N HCl) no disintegration was observed (Fig. 2A). After 1 h of dissolution in solution 2 the tablets start to disintegrate (Fig. 2B). The amount of diclofenac released in solution 1 and solution 2, respectively, over time was measured by HPLC. The diclofenac over time concentration curve is depicted in Fig. 3

Claims

1. Formulation comprising one ore more active ingredient units coated with polycarbohydratesiloxanes (PCS).

2. Formulation according to claim 1, wherein the active ingredient unit comprises one or more active ingredients and one or more excipients and/or release modifying agent.

3. Formulation according to claim 2, wherein the active ingredient unit comprises pharmaceuticals, minerals, vitamins and other nutraceuticals, and mixtures thereof

4. Formulation according to claim 3, wherein the pharmaceutical is selected from the group consisting of analgesics, anti-inflammatory agents, antiarthritics, anaesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, immunostimulant migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.

5. Formulation according to claim 3, wherein the pharmaceutical is selected from the group consisting of salicylates, in particular acetylsalicylic acid, amoxiprin, benorylate/benorilate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, and salicylamide; arylalkanoic acids, in particular, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, and tolmetin; 2-arylpropionic acids, in particular ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin. pirprofen. sυprofen, or tiaprofεnic acid; N-arylanthranilic acids, in particular mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid; pyrazolidine derivatives, in particular phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone; oxicams, in particular piroxicam, droxicam, lornoxicam, meloxicam, or tenoxicam; COX-2 inhibitors, in particular celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, or valdecoxib; sulphonanilides, in particular nimesulide; licofelone; and omega-3 fatty acids.

6. Formulation according to any of claims 1 to 5, wherein the active ingredient unit is selected from the group consisting of tablets, caplets, pills, hard or soft capsules, lozenges, sachets, pastilles, micro-pills, granules, beads, pellets, micropellets, powders and mini -tablets.

7. Formulation according to any of claims 1 to 6, wherein the PCS is the product of a hydrolysis condensation reaction (HCR) of a cyclic carbohydratesiloxane of the general formula: Si_nO_n(OH)_x(OR)_2n-X is formed wherein n is 3, 4 or 5 and x is 1, 2 or 3; wherein R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted.

8. Formulation according to claim 7, wherein the alkyl is selected from C₂ to C₁₀ alkyl, optionally substituted, preferably ethyl, 1 -propyl, 2-propyl, glyceryl, 1 -butyl, 2-butyl, tert-butyl or mixtures thereof.

9. Formulation according to any of claims 1 to 8, wherein the coat has a thickness of between 1 μm to 2 mm.

10. Formulation according to any of claims 1 to 9, wherein the active ingredient unit comprises one or more coatings beneath and/or on top of the PCS coating.

11. Formulation according to claim 10, wherein the coat is on top of the PCS coating and is an enteric coating.

12. Formulation according to claim 11, wherein the enteric coating comprises methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate. hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or mixtures thereof.

13. Formulation according to claim 6, wherein the micro-pills, granules, beads, pellets, micropellets, and mini-tablets are contained in caplets, pills, hard or soft capsules, syrups, suspensions, lozenges, sachets, or pastilles.

14. Method for producing a polycarbohydrateoxysiloxane (PCS) coating comprising the steps:

(c) carrying out a first hydrolysis condensation reaction (HCR) of one residue X of one or more identical or different Si-compounds of the following formula (I)

SlX_mY_n

(d) carrying out a second HCR, wherein the material obtained in step (a) is reacted while removing the solvent until a cyclo RO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-X is formed wherein n is 3, 4 or 5 and x is 1, 2 or 3; and (c) carrying out at least a third HCR, wherein the material obtained in step (b) is reacted to obtain a maturated PCS, wherein R in each instance is independently selected from the group consisting of alkyl, alkenyl, alkoxy and acryl, optionally substituted.

15. Method according to claim 14 , wherein m = 4 and alkyl is C₂ to Ci₀ alkyl, optionally substituted.

16. Method according to claims 14 or 15, wherein the Si compound according to formula (I) is tetraethoxysiloxan (TEOS).

17. Method according to claims 14 to 16, wherein the ratio of the molar equivalents (R- factor) of water to Si-compound(s) of formula (I) in the solvent is between 0.5 to 2.0 preferably 0.7 to 1.8.

18. Method according to claims 14 to 17, wherein the reaction of step (a) is catalyzed by acid addition and at an initial pH of less than pH 7.

19. Method according to claim 18, wherein the pH of less than pH 7 in step (a) is obtained with diluted nitric acid or (b) solutions or mixtures of (i) a physiologically acceptable organic acid and (ii) a substrate for nitric oxide synthetase (NOS).

20. Method according to claims 14 to 19, wherein step (b) is carried out at a pressure and/or temperature allowing evaporation of the solvent and/or of the alkanol formed.

21. Method according to claims 18 to 20, wherein the acidity is reduced in step (b).

22. Method according to claims 14 to 21, wherein after step (b) and prior to step (c) the material obtained in step (b) is cooled down to a temperature at or below +10°C.

23. Method according to claims 14 to 22, wherein step (c) is carried out until a viscosity of 30 to 55 Pa - s is reached.

24. PCS coating producible by the method of claims 14 to 23.

25. Method for producing a formulation comprising one or more active ingredient units comprising the steps of claims 14 to 23 and further comprising the step:

(d) applying the material obtained at the end of step (b) or the material formed during step (c) to the surface of an active ingredient unit.

26. Method for producing a formulation comprising one or more active ingredient units comprising the steps:

(e) providing cyclo RO-siloxanol of the of the general formula: Si_nO_n(OH)_x(OR)_2n-X, wherein n is 3, 4 or 5 and x is 1, 2 or 3 and R is selected from the group consisting of alkyl, alkenyl, alkoxy and acryl. optionally substituted or a maturated PCS derived therefrom by at least one further HCR and (f) applying the material to the surface of an active ingredient unit.

27. Method according to claim 26, wherein at least one further HCR is carried out, if a cyclo RO-siloxanol is provided in step (a).

28. Method according to claims 25 to 27, wherein the viscosity of the material applied is between 1 Pa ^• s and 70 Pa ^• s.

29. Method according to claims 25 to 28, wherein the material is applied to the active ingredient unit by fluidized bed granulation, spray drying or dip coating.

30. Method according to claims 25 to 29, wherein the active ingredient unit is selected from the group consisting of tablets, caplets, pills, hard or soft capsules, micro-pills, micro-beads, granules, beads, pellets, micro-pellets, and mini-tablets.

31. Formulation producible by a method according to claims 25 to 30.

32. Formulation of claims 1 to 13 or claim 31 for medical use.

33. Use of a PCS coating to protect active ingredient units from degradation or dissolution in acidic environment.