RU2412694C2 - pH-CONTROLLED PULSE DELIVERY SYSTEMS, METHODS FOR PRODUCING AND USING THEREOF - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pH-controlled pulse delivery system according to the invention, contains a nucleus enclosed by an external coating. Said nucleus contains an active substance which is preferentially a pharmaceutically active substance. Said external coating contains a pH-sensitive coating material embedding a swelling ingredient of water swell equal to at least 1.1 in relation to own weight. Said swelling ingredient is present in aforesaid coating in an amount which depending on particle size and structure of the coating forms a coating with a leakless system. The pH-controlled pulse delivery system aims at pH-related place-specific delivery of an active substance preferentially to a large intestine or a duodenum.

EFFECT: invention allows fast release of the active substance owing to the presence of the swelling ingredient in the external coating.

15 cl, 6 dwg, 8 tbl, 5 ex

Description

The invention relates to delivery systems that enable pulsed release of substances, such as a drug substance, in response to a change in pH. More specifically, it relates to the administration of drugs into the gastrointestinal tract, in particular the provision for the specific delivery of drugs to the intestines through oral administration. A pH-dependent release system is proposed that allows the rapid release of drugs under the influence of intestinal pH. The drug delivery system can completely collapse in a short period of time, allowing delivery of almost the entire volume of the drug substance to the desired location / segment. This is achieved by surrounding the drug with a layer of pH-sensitive coating containing a swelling component. The coating structure is such that the swellable component is incorporated into the continuous matrix of a pH-sensitive coating polymer at a concentration below the filtration threshold. As soon as the outer layer of the enteric coating begins to deteriorate when the pH changes, the LCD juice can reach a swelling agent that swells sufficiently to accelerate further complete destruction of the membrane and, as a result, causes the release of the drug substance in the target area.

Since the invention is illustrated using a pH dependent delivery system, it will be apparent to one skilled in the art that the scope of the invention is not limited to pharmaceutical or dosage forms. Rather, the invention can be used in any situation in which a rapid release of a substance in response to a change in pH is desired. Examples of such areas are crop protection or washing detergents.

Specific drug delivery to a selected location or segment of the GI tract is desirable in the treatment of a wide range of different diseases and conditions. It is especially desirable to be able to deliver drugs so that they are directed to specific segments of the GI tract. Targeted drug delivery to certain segments of the GI tract provides the possibility of local treatment of GI diseases, thereby reducing the side effects of drugs or the inconvenient and painful direct delivery of drugs. This specific delivery also greatly enhances the effectiveness of the drug substance and makes it possible to reduce the minimum effective dose. Moreover, targeted delivery to individual parts of the GI tract can be advantageous when the absorption of the drug into the circulatory system is limited to only part of the GI tract. In such cases, the absorption can be increased if the drug substance is delivered in a fully pulsed manner to the inside of the absorption area of the LC tract, as this could increase the absorption driving force where it is especially needed.

Significant fluctuations in pH values are observed in the GI tract and taking values from about 1 in the stomach, 6.6 in the proximal (upper) part of the small intestine to peak values of 7.5 in the distal part of the small intestine (Evans et al., 1988, Gut, 29 : 1035).

Historically, the difference between the pH of the stomach and small intestine has been used for the oral delivery of drugs to the intestinal tract using a pH-sensitive polymer coating. The delivery of drugs to places after the stomach is especially desirable for drugs that are destroyed by the action of an acidic environment or enzymes of the stomach or for drugs that cause adverse effects with local activity in the stomach. The low pH of the stomach and the presence of digestive enzymes have led to the development of dosage forms for oral administration of the drug in which the drug is supplied with an enteric coating.

Enteric-coating materials exhibit resistance to gastric fluids, but are readily soluble in intestinal fluids. Enteric-soluble materials are primarily weak acids containing acidic functional groups that are capable of ionization at elevated pH values. At a low pH of the stomach, enteric soluble polymers are protonated and - because of this - insoluble. With increasing pH in the intestinal tract, these functional groups ionize, and the polymer becomes soluble in intestinal fluids. Thus, an enteric-soluble thin polymer coating allows coated solid forms, for example, a capsule containing a drug, to pass intact through the stomach into the small intestine, where the drug is released in a pH-dependent manner. The drug substance may become available for absorption in the circulatory system or locally in the LCD tract, where it causes its pharmacological effect.

Intestinal soluble polymers currently used to coat oral dosage forms include cellulose, vinyl and acrylic derivatives. The most common enteric coatings are methacrylic acid copolymers (Eudgartis), cellulose acetate phthalate, cellulose acetate succinate and maleic acid styrene-copolymers (Ritschel, WA, Angewante Biopharmazie, Stuttgart (1973), pp. 396-402, GA. 396-402; GAgyilih; et al., "Polymers for Enteric Coating Applications" in Polymers for Controlled Drug Delivery, Tarcha, PJ ed., CRC Press, (1991) Boca Raton, pp. 39-66).

To achieve a position-specific delivery to specific areas of the gastrointestinal tract, several strategies exist. Time-dependent delivery systems have the property of releasing a drug substance after a certain period elapsing from the moment the system contacts the water (swelling of the system). However, the reliability of such systems is limited by significant changes in transit time along the LC path (OCTT). If the passage speed is greater or less than expected, the drug substance may be released in the wrong place or outside the absorption area of the drug substance. The second strategy takes advantage of the difference observed in the surrounding environment at different points in the LC tract, thus circumventing the problems of OCTT differences. There are two different sub-strategies: systems that respond to bacterial enzymes can be used to direct to the rectum, while systems that respond to pH changes can be used to direct to different areas of the LCD tract. Bacterial enzyme dependent systems have two main limitations. First of all, the bacterial flora can vary from individual to individual; if the desired bacterium is not present in the patient, the drug may not be released at all. Moreover, the release from such systems is usually quite slow and the pulsed type of release is difficult to achieve. pH-dependent systems have the advantage of being site-specific. Just like systems dependent on bacterial enzymes. They depend little on the transit time through the LCD tract (orocaecal transit time (OCTT)), which may vary from patient to patient. Moreover, they are independent of the presence of bacteria. Finally, pH-sensitive polymers making site-specific release available are readily commercially available.

However, an important limitation of this technique is the fact that the dissolution of the pH-sensitive coating occurs slowly at pH values that are only slightly above a predetermined value. Since fluctuations in pH in the intestine can lead to a situation in which the pH of the environment is slightly higher than the set value in the desired area, dissolution / destruction of the coating is often slow. As a result, the kinetics of drug release in a given desired region often has a delay time of several hours, or the drug substance will be slowly released over several hours. Since, from physiology, the time spent in a given place is limited, this delay or slow release significantly reduces the amount of drug substance that is effectively delivered to a given area. Moreover, the profile of bowel contractions varies in individual patients and during various diseases. The combination of this with a delay time or a slow release of the drug substance makes the release site of the drug substance difficult to control. For example, it can vary from the ileum to the colon.

Thus, an object of the present invention is a reliable option pH-dependent delivery system - pulse delivery. A pulsed drug release triggered by a change in pH could provide a quick and site-specific drug release in the intestine. It has advantages in cases where it is desirable to achieve high concentrations of the drug substance in certain areas of the intestine for a short period of time, either for treatment or for influencing the concentration gradient, which will increase the absorption of the substance in the absorption zone.

The inventors of the present invention unexpectedly discovered that this goal can be achieved if a destructive (e.g., swellable) component is included in the structure of the pH-sensitive coating layer. As shown here, a new type of composite coating significantly increases the rate of drug release compared to conventional pH-sensitive coatings that do not contain a destructive agent. Thus, the invention provides a pH dependent pulse release system (PPRS) comprising a core surrounded by a coating layer, where the core is an active substance and the coating consists of a pH sensitive coating material with a swellable component incorporated.

Without going into theory, it is assumed that the swelling material is included in the entire structure of the pH-sensitive polymer. The beginning pH-dependent destruction of the composite coating as a result of dissolution of the pH-sensitive polymer makes it possible for water to be absorbed by particles of a swellable component located directly below the surface of the coating. The outer layer of the coating layer is destroyed by swelling of the swellable component, and the underlying particles of the swellable component, as well as the wetted polymer, become accessible to the action of the liquid. Thus, the coating polymer will be actively destroyed, which will lead to rapid and complete destruction, followed by pulsed release of the drug substance. Further information on the mechanism of pH-dependent pulsed release of drugs according to the invention is presented in the diagram in FIG. 1 and in the description of the drawings.

As used herein, the term “swellable component” refers to a mixture of compounds capable of swelling under the influence of liquids based on water. In the field of drug preparation technology, it is sometimes used as a “destructive component”. This is a hydrophilic material of natural, synthetic or semi-synthetic origin. The ability of the swellable component used for the practical application of the invention to swell may vary. The ability to swell is expressed as the amount of water that the component can absorb, in terms of its dry weight. For example, a swellable component with a swellability of 10 can absorb 10 times the mass of water. In one embodiment, the swellable component has a swellability of 1.1 or more, preferably 5 or more, more preferably 7 or more. In general, the higher the swelling ability of the swellable component in the enteric coating, the faster and more effective the destruction of the coating layer at the beginning of the pH-dependent destruction (dissolution) of the outer layer of the enteric coating. Thus, the swellable component preferably has the ability to collect water weighing more than 7 times its own, for example, at least 10 times, about 15 times, or even more, about 20 or 25 times.

Suitable swelling agents for this invention include sodium starch glycolate (Primojel ™, Explotab ™) or cross-linked carboxymethyl cellulose (Ac-Di-Sol ™). However, it will be apparent to one skilled in the art that other types of swellable substances, already known or those to be discovered, are also encompassed. Moreover, a combination of two or more components may be used.

In one embodiment, sodium starch glycolate is used as the swellable component. Sodium glycolate starch is used in oral preparations as a destructive agent (disintegrant) in capsules or tablets. Destruction occurs with rapid capture of water, followed by rapid and extensive swelling. However, its use in the matrix of a pH-sensitive stable enteric coating, as described herein, was not previously known. Sodium starch glycolate is the sodium salt of carboxymethyl starch ether. The molecular weight is usually about 500000-11000000. It is a very fine, white or colorless, easy-to-pour powder, odorless or almost odorless. It is practically insoluble in water and insoluble in most organic solvents. It consists of spherical or oval granules, 30-100 microns in diameter, partially from less spherical granules 10-35 microns in diameter. In a preferred embodiment, Primojel ™ or Explotab ™ are used as swelling agents. Primojel is a starch with USP-NF sodium glycolate, obtained by cross-linking and carboxymethylating potato starch, followed by purification. It corresponds to the latest editions of Ph. Eur. (sodium starch glycolate types A, B and C), USP / NF (sodium starch glycolate types A and B), JPE. Both the degree of crosslinking and the degree of substitution have been optimized to maintain maximum fracture efficiency. Primojel ™ absorbs its 25th weight in water. The resulting high swelling ability combined with water permeability is the reason for its highly effective degradability.

The term “enteric coating” as used herein refers to pH stable coating materials or mixtures thereof. Examples of suitable coating materials include cellulose acetate phthalate, hydroxypropyl cellulose phthalate and EUDRAGIT ™ acrylic polymers. It also includes modern swelling hydrogels derived from neutral or advanced polymer systems (see Peppas et al., Expert Opin Biol Ther. 2004 Jun; 4 (6): 881-7 or WO98 / 43615).

In a preferred embodiment, acrylic polymers are used. In one embodiment, Eudragit® L 100 or L 100-55 are used to deliver drugs to the duodenum (pH> 5.0). For delivery to the jejunum (pH> 6.0), Eudragit® L 100 is suitable for use. In another embodiment, the combination of Eudragit® S 100 and the swellable component enables pulse release in the lower ileum and the ascending part of the colon (pH from 6.0 to 7.5). Site-specific drug delivery can also be achieved with a combination of Eudragit® S 100 and Eudragit® L-types.

The coating may also contain one or more additives, for example a plasticizer, which facilitates the formation of a polymer film and makes possible the formation of extended, easily structured and elastic layers of the coating. Suitable coating additives include polyethylene glycol (PEG), triethyl citrate (TPP), dibutyl sebacinate (DBL), tributyl citrate, diethyl phthalate and acetyl tributyl citrate. In certain aspects of the invention, the coating layer comprises Eudragit, for example Eudragit S 100, in combination with sodium starch glycolate as a swelling agent and polyethylene glycol (PEG) as a plasticizer. As demonstrated by the following examples, the release profile of a drug substance contained in a capsule coated with a layer of such a coating is pH dependent and has a pulsed release pattern.

In another aspect, the invention provides PPRS comprising a coating layer of Eudragit S 100 in combination with cross-linked carboxymethyl cellulose as a swellable component. In a further aspect, the invention comprises a coating layer of Eudragit L 100 in combination with sodium starch gluconate.

However, it is worth noting that the general idea underlying the present invention, i.e. a composite coating layer containing both a swellable component and a coating material is not limited to a particular type of coating material. Thus, the invention is not limited to known pH-sensitive coating materials, but also encompasses coating and / or swelling materials that will be opened.

The use of swellable components to achieve controlled release of a drug is known in the art. US 4,871,549 discloses a time-controlled system for the sustained release of a drug substance in which drug release is caused by rupture of the membrane after a certain period of time. The system contains a preparation containing a core, a drug, a swellable component and an outer membrane of a water-insoluble coating material. When the system enters the dissolving medium of the LC tract, water inlet and an increase in the volume of the swellable component cause a rupture of the permeable membrane. In this way, the drug substance is released after a predetermined period of time. It is emphasized that, in contrast to the present invention, the system US 4871549 does not depend on the pH of the gastrointestinal fluids. Moreover, the swellable component is present as a separate, inner layer and is not included in the outer coating layer.

Alza Company’s two-phase OROS ™ system was developed for the time-controlled, pulsed delivery of water-soluble and water-insoluble drugs to a specific location in the GI tract (for example, to the colon). For example, OROS-CT ™ is based on the swelling properties of an isolated osmotic core, providing a pH-independent, time-controlled release of the drug.

European patent EP0384646 B1 describes a drug composition that is located inside a water-insoluble capsule body and sealed with a hydrogel plug. This drug delivery system is known as PULSINCAP ™. When administered orally, the capsule coating dissolves in the gastric juice, and the hydrogel plug swells. At a given or specific time, the swellable plug is removed from the PULNICAP ™ dosage form and the drug contained in the capsule is released.

European patent EP1021171 also relates to a time-controlled drug delivery system. It consists of a core containing a drug and a swelling agent, and a coating surrounding the core. The core consists of a water-insoluble, hydrophobic carrier, in which dispersed material is included. In the presence of water-based liquids, the dispersed material forms channels from the outer coating layer to the core. Channels control the rate at which water enters the core. The core material swells, breaks through the coating and quickly collapses to release the drug. There are a number of significant differences between EP1021171 and the present invention. Firstly, the hydrophobic film and the hydrophilic dispersed material are insoluble in the liquids of the LC tract. Thus, unlike the invention, the coating will remain undissolved regardless of pH. Secondly, the dispersed material is included in the carrier material to create channels through which water can reach the swelling core. The rate at which time-dependent delivery systems release the drug contained depends on the thickness of the coating and the amount of dispersed material, i.e. number of channels. Thus, the amount of dispersed material in the coating is critical at the time of drug delivery, for example 4 or 6 hours after oral administration of the drug. However, the present invention relates to drug delivery systems in which the moment of drug release is determined by the pH of the environment; the presence of a swellable component does not affect the onset of drug release, only accelerating the process after it has been started by a change in pH. Fourth, in EP1021171, the swellable core provides strength for the ultimate destruction of the surrounding coating. The system of the invention is clearly independent of the core. Fifthly, EP1021171 requires the formation of a transmissive structure of a hydrophilic dispersed powder inside a hydrophobic carrier to guarantee effective channel formation. As will be described in detail below, in the mixed enteric coating of the invention, the formation of a transmissive matrix should not be allowed, as this will lead to an immediate pH-independent release of the drug. It is important for the system of the invention to use an amount of swellable agent below the transmittance threshold.

WO 98/13029 discloses an Oral Delayed Immediate Release containing a compressed core containing one or more active substances surrounded by a coating containing one or more polymeric materials in which the release of the active substance (s) from the core due to breakdown of the coating after a certain delay time; the aforementioned core containing one or more instantly released carriers and not having significant swelling properties under the action of LC liquids, and the above polymer coating material, which is substantially insoluble and / or indestructible in LC liquids.

Thus, a pH-controlled pulsed release system containing a swellable component included in an impermeable form in the structure of a pH-sensitive coating material is not previously described herein.

For guaranteed pH-dependent release of the substance surrounded by the coating layer, the swellable component should be accessible to liquids only with the initial dissolution of the structure in which it is included. Thus, the swellable component must first be separated from the liquids by a pH-sensitive coating material to prevent premature swelling and destruction of the coating layer. It has been found that this can be achieved by using a suspension of the swelling agent in a solution of a pH-sensitive coating material, such as enteric polymer coatings or other polymer coatings. The coating suspension contains a solvent or mixture of solvents in which the coating material is soluble and in which the swellable component is insoluble and not subject to swelling. Thus, the swelling agent particles in the coating suspension are surrounded by dissolved coating material. A coating suspension may be applied to the substance to be coated, for example, by spraying. After removal of the solvent or mixture of solvents, the resulting coating layer consists of a coating material in which particles of the swellable component are included.

In a preferred embodiment, the coating suspension is prepared using an organic solvent. Most pH-sensitive coating materials are soluble in organic solvents such as acetone or isopropyl alcohol, while suitable swellable components are insoluble in organic solvents and are not swollen in these solvents. In one aspect, the coating suspension contains Eudragit as a coating material and sodium starch glycolate as a swelling component in a mixture of organic solvents with a small percentage of water, for example acetone: water (97: 3, v / v). Water is used as a plasticizer.

Since swellable particles are located on the outside of the coating layer, they can cause destruction of the coating already before reaching the desired pH value; a coating containing a swellable component may optionally be surrounded by an additional thin coating layer containing a pH-sensitive polymer without any swellable component.

The performance of the coating largely depends on the composition and structure of the coating material. Adequate properties are achieved only when there is a continuous film of a pH-sensitive polymer and the swellable component is included in a non-permeable form to prevent the coating from breaking until the desired pH value is reached. The exact amount of the swellable component in the coating layer will depend on several properties of the coating material, the physicochemical properties of the swellable component (the particle size of the material is of particular importance here), the preparation process and conditions during the process, other fillers that may be present in the coating, and so on. . The specialist will be able to experimentally determine the optimal amount of swelling component for a particular situation without undue effort, for example, using the gastrointestinal tract simulation system described in Example 1. Based on the results of initial experiments and a general knowledge of conducting systems, the specialist will be able to determine how to change the design and composition of the composition to achieve desired functionality. If, for example, the particle size of the swellable material decreases, its concentration in the coating layer must also be reduced to prevent the formation of a conductive structure of the swellable material.

In another aspect, the invention provides a method for producing a pH-controlled pulsed release system of solid substrates, comprising the steps of preparing a coating suspension in accordance with the invention, coating the solids with the suspension above, and allowing the solvent to evaporate so that a coating layer forms in which the swelling agent included in the structure of the pH-sensitive coating material. The solid substrate is easily coated with the suspension when sprayed.

Moreover, the use of the coating suspension described above makes it possible to obtain pH-controlled pulsed release systems, mainly drug delivery systems.

The pH controlled pulsed release system (PPRS) presented here, which enables pulsed release of a substance in response to a change in pH, contains a core surrounded by a coating layer, where the aforementioned core contains the active substance. A mixture of two or more active substances may also be used. The coating layer can be applied directly to the core so that the outer surface of the core will be in contact with the inner surface of the coating layer. However, it is also possible for one or more layers to separate the outer surface of the core from the inner surface of the coating layer.

In a preferred embodiment, the active substance, surrounded by a pH-sensitive coating layer, is a drug, for example a drug for the treatment or prevention of a disease. However, the active substance may also be a diagnostic substance, such as monitored molecules, for example, a stable isotope. The core containing the active substance is, for example, a capsule or tablet. A solid core containing a substance and optionally additional materials may be coated by applying a suspension of the invention. Additional materials that can be used in the preparation of nuclei containing a drug are any of those widely used in pharmaceuticals, and should be selected on the basis of compatibility with the active drug and physicochemical properties of the core. They include binders, disintegrants, fillers, surfactants, stabilizers and lubricants.

Suitable binders include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch and the like.

Suitable swellable ingredients include corn starch, pregelatinized starch, cross-linked carboxymethyl cellulose (AC-DI-SOL ™), sodium starch glycolate (Primojel, EXPLOTAB ™), cross-linked polyvinylpyrrolidone, any known pharmaceutical technology and alginic acid funds. It was shown that the introduction of a swelling destructive component not only in the coating material, but also in the core containing the drug, provides the creation of pH-sensitive drug delivery systems with a high pulse release profile.

Suitable excipients include lactose, mannitol, microcrystalline, calcium cellulose carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starch, sucrose, xylitol, lactitol, mannitol, sorbitol, calcium chloride, polyethylene glycol and the like.

Examples of surfactants are sodium lauryl sulfate, sorbitol monooleate, polyoxyethylene sorbitan monoleate, bile salts, glycerol monostearate and the like.

Stabilizers like any antioxidants, buffers, acids and the like can be used.

Examples of lubricants are magnesium stearate, glycerol behenate and sodium stearyl fumarate.

In one embodiment, the drug-containing core is a drug-filled gelatin capsule, with or without additional excipients. Typical excipients that can be added to the capsule include, but are not limited to: excipients, such as microcrystalline cellulose, bicarbonate calcium phosphate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, liquid adjuvants, such as silica, talc, or any other material that imparts fluidity to the powder, may also be added. A lubricant can then be added as needed: polyethylene glycol, leucine, glycerol behenate, magnesium stearate or calcium stearate.

The drug may be administered in tablets or granules.

A special embodiment of the present invention relates to PPRS for the delivery of active substances, for example, drugs or diagnostic molecules, to specific locations in the LC tract. Depending on the type of coating material used, the above drug delivery system is a colon specific delivery system or a duodenal specific delivery system.

In a special aspect, the invention provides colon-specific PPRS, for example, for the specific delivery of drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), cetrorelix or mesalazine (5-ASA), or diagnostic molecules, such as stable carbohydrate isotopes, into the colon the gut. The problem of targeted delivery of drugs to the colon has faced scientists over the past two decades. Originally considered as a relatively safe organ, necessary only for the absorption of water and electrolytes, as well as for temporary storage of feces, the colon has recently been an object of increasing importance for human physiology and for drug delivery. The scientific interest in delivering drugs to the colon was fueled by the need for better treatment of colon diseases: from severe constipation and diarrhea, debilitating inflammatory bowel diseases (ulcerative colitis and Crohn's disease) to colon carcinoma, the third most common form of cancer, as in men , and in women. Targeted delivery of drugs to the colon thus provides a guarantee of treatment at the site of the disease, lowering the dose and reducing systematic side effects. In addition to local treatment, the colon can also be used as a place for drugs to enter the bloodstream for systematic therapy. For example, drugs (e.g., proteins or proteins) that are readily degraded or poorly absorbed in the upper parts of the GI tract can be predominantly absorbed in the colon due to lower levels of digestive enzymes compared to the small intestine. Moreover, drug delivery to the colon can also be used as a means of achieving time-distributed therapy of diseases that are sensitive to circadian rhythms, such as asthma or arthritis.

While oral administration is preferred for administration of drugs for administration to the colon, it has its problems. The large intestine constitutes the most distant part of the GI tract and orally administered formulations should ideally have a slow release (or inhibit release) of the drug in the upper GI tract, but release the drug immediately upon entry into the colon. Effective protection of the drug from diverse and hostile conditions in the stomach and small intestine can be achieved by using pH-sensitive coatings. However, the low fluid content and viscous nature of the contents of the colon prevents the dissolution and release of drugs from currently known colon-specific formulations. The inventors of the present invention unexpectedly discovered that the latter problem can be solved by introducing a swellable component into the coating layer.

The inventors used a gastrointestinal simulation system (GISS; see Example 1) to study the kinetics of drug release on a mesalazine model (5-ASA) from capsules coated with a pH-sensitive enteric coating containing different amounts of swelling component. It was shown (see Example 2) that the percentage of swellable component in the coating layer affects the onset and the pulsed nature of the release profile of the pH-controlled pulsed release system of the invention. GISS phase IV drug release simulating specific release in the colon was shown to be 90% of the total release if 4 or 5% of the swellable Primojel component was included in a coating suspension containing Eudragit and PEG. The 10% Primojel content in the coating suspension leads to 56% drug release in phase IV. Thus, for this specific application of PPRS in accordance with the invention, this is the optimum level of swelling component in the coating layer.

In a further embodiment, the invention provides PPRS specifically delivering a drug, for example L-Dopa (also known as levodopa) to the duodenum. Oral administration of L-Dopa is currently the preferred treatment option for dopamine deficiency in the brain causing parkinsonism. The best absorption of L-Dopa occurs in the duodenum and proximal jejunum. The pharmacokinetics of L-Dopa is such that fluctuations in its level are observed in the blood, which leads to fluctuations in the motor functions of suffering patients. Gastric-resistant granules (containing L-Dopa) are based on a floating coating with a pH-sensitive coating with a pulsed release, as described here, can be used to maintain a constant amount of drug and absorption zone, thereby preventing the effects of fluctuations in motor functions in this pharmacotherapy of Parkinson's disease.

In another embodiment, site-specific delivery includes the delivery of the active substance to specialized tissue of the small intestine. For example, the invention provides PPRS for delivering an active substance, like a vaccine, to Peyer's plaques. Peyer's patches are a collection of large oval-shaped lymphoid tissues located in the mucus-secreting lining of the small intestine. These lymphoid nodules are especially numerous in the lowest part of the small intestine, which passes into the larger section of the intestinal tract, an area of the digestive system known as the ileum. They detect antigens and mobilize highly specialized white blood cells, called B-cells, to produce antibodies designed to attack foreign particles. Peyer's plaque targeting can be achieved by using a coating consisting of a polymer such as Eudragit S100 coupled to a swellable component such as cross-linked carboxymethyl cellulose (AC-DI-SOL ™) and sodium starch glycolate (Primojel, EXPLOTAB ™).

Drawing captions

Figure 1. Scheme of the hypothetical mechanism of action of the swellable component included in the coating layer. In stage 1, the drug delivery system is exposed to intestinal fluids with a pH> 7. The pH-sensitive polymer material of the coating layer begins to dissolve / collapse. At stage 2, microcracks and leaks of the coating layer are formed in such a way that the particles of the swellable component immediately below the surface are wetted. The absorption of liquid by the swelling component leads to a sharp increase in its volume (stage 3), accompanied by further destruction of the coating layer, increased penetration of the liquid into the coating layer and swelling of the swelling component. This cascade is responsible for the rapid and complete degradation of the coating layer so that the surface of the core, for example, a capsule with a drug, becomes accessible to the environment (stage 4). There is a gradual transition from pH-dependent destruction to destruction based on the action of water-based liquids on the swelling component.

Figure 2. The release profile of the various registered 5-ASA dosage forms obtained using the gastrointestinal tract simulation system (GISS) described in Example 1. Phase I is gastric stimulation, phase II is the duodenum, phase III is the distal ileum, phase IV - colon.

Figure 3. Averaged release profile of 6 capsules containing 5-ASA coated with a pH-sensitive polymer (Eudragit S100). The release of 5-ASA was determined during the use of the GISS system described in example 1. For more details, see example 2.

Figure 4. Averaged release profile of 6 capsules containing 5-ASA coated with a pH-sensitive polymer (Eudragit S100) and 5% swelling component (Primojel ™). The release of 5-ASA was determined during the use of the GISS system described in example 1. For more details, see example 2.

Figure 5. Colon specificity of a pulsed pH-dependent release system (PPRS) containing a gelatin capsule with 50 mg of 5-ASA drug, coated with a coating layer (20 mg / capsule) 7% Eudragit S100 / 1% PEG6000 and the indicated percentage of swelling component (Primojel ™). CRP-TQR means the total amount released, which is the percentage of 5-ASA released in phase IV representing the colon, of the total amount of 5-ASA released in phases I to IV. The percent release in the colon of the total dose (CRP-TD) is the percentage of the total dose released in phase IV. For more details, see example 2.

6. The effect of the percentage of swellable component in the coating suspension on the rate of pulsed release of the drug. The rate is determined by measuring the period of time required to release an average of 50% (T ₅₀ ) or 70% (T ₇₀ ) of the total dose of the drug with respect to the time 0 (T ₀ ) at which <5% of the drug release was detected.

Examples

The present invention will be further illustrated by the following examples. These examples are not limiting and do not limit the scope of the invention. It will be apparent to one skilled in the art that many different combinations of pH-sensitive coating materials and swellable components are suitable for use in pH-controlled pulsed release systems of the invention; their specific relationship can be determined empirically.

Example 1: Gastrointestinal Simulation System (GISS)

An example describes a gastrointestinal simulator system that was used by the present inventors to study the drug release profile of a pH-controlled pulsed drug delivery system of the invention.

The mesalamine drug (5-ASA) was used as an experimental drug to evaluate and validate the GISS system. 5-ASA is used in the treatment of ulcerative colitis and is rapidly absorbed in the proximal part of the intestine. We tested the following commercially available 5-ASA oral dosage forms: Salofalk® tablets, Salofalk® granules, Asacol® tablets, Pentasa® tablets and granules.

GISS is a solubility test based on the pharmacopoeial plate technique (apparatus II, Prolabo, Rhone-Poulenc, Paris, France), as described in USP 26 and Ph. Eur. IV. During the test, the dosage form undergoes four phases of exposure, simulating sequentially: the stomach, duodenum and proximal colon. Table 1 describes these phases, as well as the bio-relevant medium used. The plate was rotated at a speed of 50 rpm and the temperature of the system was maintained equal to 37 ° C.

Table 1
Description of the four phases of GISS Phase GI segment Volume (ml) Duration of stay (h) pH Osmotic concentration (mosmol / kg) I Stomach Pepsin-Free Artificial Gastric Juice (USP 26) 500 2.0 1.2 ± 0.10 150 ± 25 II Jejunum Pepsin-Free Artificial Intestinal Juice (USP 24) + Sodium Chloride 629 2.0 6.8 ± 0.10 250 ± 50 III The ileum (distal section) Pepsin-Free Artificial Intestinal Juice (USP 23) + Sodium Chloride 940 0.5 7.5 ± 0.10 250 ± 50 IV Large intestine (proximal) Artificial Colon Juice 1000 1,5 6.0 ± 0.10 250 ± 60

The buffer capacity was tested by measuring pH in GISS without or in the presence of 5-ASA. It was also tested whether the osmolarity changes during the dissolution test.

Release measurement.

The release profile of the modified oral dosage form was measured by spectrometric measurement of 5-ASA concentration using an Ultraspec 4052 TDS instrument (LKB, Zoetermeer, The Netherlands). Specific absorption of 5-ASA was detected (n = 5) at a wavelength of 331 nm (Table 2). If the obtained concentration value fell outside the linear measurement region, the absorption was measured separately, after diluting the sample with 3N hydrochloric acid and subsequent measurement at 303 nm. The specific absorption of 5-ASA is 236.

table 2
Specific Absorption of 5-ASA per Phase Phase Specific Absorption at λ = 331 nm I 17.3 II 209.5 III 218.2 IV 161.4

Calculation.

The release rate was calculated by dividing the amount of released substance per phase by the time spent in the phase. Colon release selectivity can be expressed using 3 different parameters. The percentage of release in the colon of the total amount released (CRP-TQR), which is the percentage released during phase IV, of the total release in phases I through IV. Secondly, the percent release in the colon of the total dose (CRP-TD). As a percentage of the dose released in phase IV. Thirdly, the colon specific dose (CSR) is a dose-independent parameter indicating selective release of the dose in the colon relative to the dose released in the other three phases of GISS. It is calculated by dividing the fraction liberated in phase IV by the total fraction liberated in the three preceding phases.

Results.

Gastrointestinal Simulation System

An important aspect of the in vitro dissolution of pH controlled dosage forms is that it is possible to influence the pH of the released compound itself. Table 3 shows that GISS has sufficient buffer capacity to maintain pH values within the required range (see Table 1) during the release of 5-ASA in four phases. Moreover, osmolarity remains at the required level (Table 1), regardless of the presence of 50 mg of 5-ASA.

Table 3
Average pH ± standard deviation
measured in GISS n I II III IV Empty 2 1.21 ± 0.01 6.85 ± 0.03 7.54 ± 0.01 6.29 ± 0.00 500 mg 5-ASA 2 1.22 ± 0.00 6.67 ± 0.03 7.31 ± 0.05 6.10 ± 0.05 Salofalk ^(r) , MSR 500 mg tablet 6 1.16 ± 0.01 6.85 ± 0.02 7.52 ± 0.05 nm ¹ Salofalk ^(r) , Granustix
in sachet 1000 mg 6 1.18 ± 0.01 6.86 + 0.01 7.67 + 0.01 5.89 ± 0.01 Asacol ^(r) , tablet
MSR 400 mg 5 1.12 ± 0.00 6.63 ± 0.06 7.25 ± 0.05 6.12 ± 0.06 Pentasa ^(r) , 500 mg, sustained-release tablet 6 1.14 ± 0.02 6.65 ± 0.02 7.34 ± 0.03 5.97 ± 0.04 Pentasa ^(r) , granules in sachet 1 g 6 1.23 ± N / D 6.79 + N / A 7.54 + N / A 5.77 ± N / D ¹ not measured

3.2. Release Profiles

Figure 2 shows the release profiles of the investigated products. As expected, pH-sensitive coated products (Salofalk® tablets, Salofalk® granules and Asacol® tablets) generally do not release 5-ASA in a simulated stomach under the most rapid conditions (phase I). Moreover, it has been shown that Salofalk® tablets release 5-ASA more proximal than Asacol® tablets. Both did not release a large amount of 5-ASA in the simulated colon. Pentasa® tablets as well as Pentasa® granules released a significant amount (50-70%) of 5-ASA within 2 hours in SGFsp (USP 26). Moreover, both tablets and Pentasa® granules released 5-ASA in a simulated stomach 3-5 times faster than in simulated small and large intestines (Table 4). Salofalk® pellets exhibit a delay time after which release begins with 0 order kinetics. All products acted in accordance with their pharmaceutical technology description.

Table 4
Release rates during different phases for the products studied (reduced to a dose of 500 mg) Release Rate (mg / min per phase) I II III IV Salofalk ^(r) , MSR 500 mg tablet 0,0 4.3 0.8 0,0 Salofalk ^(r) , Granustix in a sachet of 1000 mg 0.1 1,2 2.5 0.4 Asacol ^(r) , 400 mg MSR Tablet 0,0 3.3 2.2 0.2 Pentasa ^(r) , 500 mg, sustained-release tablet 2.1 0.5 0.6 0.1 Pentasa ^(r) , granules in sachet 1 g 2,8 0.6 0.6 0.2

Table 5 presents colon selectivity for each product. Data indicate that colon selectivity is low. Only the bottom product exhibits a certain level of colon selectivity.

Table 5
Values of CRP-TQR and CRP-TD for the investigated products Product CRP-TQR CRP-TD Salofalk MSR 500mg Tablet 0,0% 0,0% Pentasa 500 mg Sustained-Release Tablet 3.3% 2.2% Asacol 400mg MSR Tablet 3.8% 3,7% Pentasa, granules in sachet 1 g 4.7% 4.1% Salofalk, Granustix Sachet 1000 mg 14.8% 6.8%

Conclusion

The release profiles of all products are in accordance with their technological and available data obtained in vivo . The percentage of dose released in the simulated colon is small for all products. GISS is a robust system capable of distinguishing between oral medications with various types of modified release.

Example 2. Development of a pH-controlled pulsed release system (PPRS)

This example demonstrates the beneficial effect of incorporating a swellable component (in this case, solid sodium glycolate starch under the trade name Primojel) in the coating layer of a pH-sensitive enteric coating material.

Materials and methods.

A standard coating solution was prepared containing 7% polyacrylane resin (Eudragit S100) and 1% PEG6000 in a mixed solvent of acetone / water [97: 3; by volume]. Various amounts (1, 2, 3, 4, 5, or 10% (w / v)) of Primojel were added to the standard coating solution to obtain various coating suspensions. In a second experiment, the capsules were coated using an improved coating procedure. Various amounts (4, 5, 6, 7% w / v) of Primojel were added to the standard coating solution.

A coating suspension was applied by spraying (Capsule Coater, Labo Tech) onto hard gelatin capsules in an amount of 29 g of a coating suspension per 20 capsules. Capsules contained 50 mg of 5-ASA and Avicel ™. The size of the charge was 20 capsules. Following the coating step, the capsules were heated for 1 hour at 50 ° C. to evaporate the solvent mixture and obtain a polymer film, such as a composite coating layer was formed around the capsule.

Tests performed.

The GISS described in Example 1 was used to study the 5-ASA release profile for each series of coated capsules. The averaged release profile was determined in real time by determining every 3 minutes the concentration of 5-ASA using spectrophotometry at 331 nm (n = 6).

Calculations.

The release rate was expressed as the time required to release 50% (T50) relative to 70% (T70) of the contents calculated from the last measurement with a value below 5%. Colon selectivity was expressed using two parameters:

the percentage of release in the colon of the total amount released (CRP-TQR),

colon release rate of total dose (CRP-TD)

Results.

Figure 3 shows the geometric mean value of the release profiles of five different capsules that were coated with standard coating solutions, i.e. without swelling component. Figure 4 shows the average release profile of six different capsules coated with 20 g of a coating layer containing a swellable component. Capsules coated without a swelling component showed insufficient release of 5-ASA (50.4%) after 360 min in GISS. In addition, there was a large spread in the released dose (from 5 to 98%). The addition of a swellable component to the coating suspension resulted in a pulsed release profile, after a delay time of about 240 minutes. The presence of a swellable component in the coating layer clearly increased the rate of release of the drug from the capsule, decreased the variability between the capsules, and increased CRP-TD. Table 6 shows all the data.

Table 6
Characteristics of coated capsules containing Primojel swellable component in different concentrations %
Primojel t50 t70 Release (t = 270) Release
(t = 360) CRP-TD CRP-TQR 0% 78 min 135 min 7.8% 58.2% 50.4% 94% one% 106 min 151 min 1.5% 31.4% 29.9% 96% 2% 397 min 556 min 1.7% 14.1% 12.4% 88% 3% 167 min 242 min 3.6% 29.0% 25.4% 90% four% 108 min 501 min 9.2% 48.8% 39.6% 80% 5% 38 min 45 min 16.2% 98.2% 82.0% 81% 10% 36 min 74 min 28.8% 77.6% 48.8% 56%

The effect of the amount of swelling component in the coating layer on colon-specific drug release is graphically displayed in FIG. 5. Colon selectivity was expressed in CRP-TQR and CRP-TD (for abbreviations see Example 1).

Capsules coated with a standard coating solution containing 0-5% Primojel exhibit a CRP-TQR of more than 80%. CRP-TQR is lower in capsules coated with 10% Primojel in a coating suspension. Only at a concentration of 5% Primojel substance, a large fraction of the total dose is released in the simulated proximal part of the colon, as can be seen from the high CRP-TD value. On average, 82% of the total dose of 5-ASA is released in phase IV of this GISS, while other tested capsules release only up to 50% in phase IV.

6 shows the effect of the percentage of Primojel in the coating suspension on the pulsed release rate of the drug. This rate is determined by measuring the period of time lost to release approximately 50% (T ₅₀ ) or 70% (T ₇₀ ) of the total dose of the drug, relative to the time zero (T ₀ ), in which less than 5% of the drug is detected.

Example 3. PPRS optimization

This example describes the optimization of the procedure described in example 2 for the production of pH-controlled pulsed delivery systems. Optimization involves the primary mechanical aspects of the coating process, such as reducing the inlet and outlet tubes, pre-starting the pump, and using standardized glass products and mixers to prepare the coating slurry. Moreover, the swellable component was included not only in the coating layer, but also in the core.

Materials and methods.

Avicel-filled gelatin capsules 50 mg of 5-ASA and 5% Primojel are coated with a coating slurry containing 7% Eudragit S100 and 1% PEG: 000 in acetone / water [97: 3]. The coating suspension further contains 4.5.6 or 7% Primojel. Capsules were coated with 20 g of a coating suspension as described in Example 2. Each batch containing 20 capsules was tested in the GISS described in Example 1 to determine the release profile of 5-ASA.

Results.

Colon selective release was expressed as CRP-TQR and CRP-TD (see Example 1 for an explanation of these abbreviations). As shown in Table 7, drug release from capsules coated with 4 or 5% Primojel 90% material occurred in GISS phase IV (CRP-TQR). The remaining was released in phase III. The drug release in the simulated proximal colon from a capsule coated with 4 or 5% Primojel was 67% and 59% of the total dose, respectively (CRP-TD). Both parameters decreased with increasing percentage of Primojel in the coating due to a reduction in the opening time of the coating. For capsules with 6 and 7% Primojel, the onset of release occurred in the second GISS phase (T ₀ was 155 and 149 min, respectively). Early erosion led to early destruction of the coating in phase III. In contrast, T ₀ for capsules with 4 and 5% was 186 and 183 minutes, respectively.

Table 7
Measurement data of coated capsules in accordance with the improved coating procedure described in Example 3 %
Primojel T ₅₀ T ₇₀ Release (t = 270) Release (t = 360) CRP-TD CRP-TQR four% 40 min 63 min 6.4% 87.4% 81.0% 89% 5% 54 min 87 min 8.3% 78.3% 70.0% 89% 6% 30 minutes 38 min 31.0% 87.6% 56.6% 58% 7% 28 min 43 min 30.6% 87.8% 57.2% fifty%

All capsules tested had a pulsed release profile, as illustrated by the T ₅₀ and T ₇₀ values in Table 7. Capsules coated with a coating suspension of 4% Primojel released 70% of the drug within 67 minutes from the start of the release. An increase in the percentage of Primojel was accompanied by a decrease in the rate of release of the drug; The incorporation of 7% Primojel in the coating suspension resulted in an increase of T ₇₀ to 99 minutes. In conclusion, although all percentages tested showed a good pulsed release profile, concentrations of 4 or 5% of the Primojel substance worked best with respect to the release in the (simulated) colon.

Example 4

This Example describes the use of the second type of swellable components. A standard coating solution was prepared containing 7% polyacrylate resins (Eudragit S100) and 1% PEG6000 in an acetone / water solvent mixture [97: 3; by volume]. Various amounts (0.3 and 5%) of Ac-Di-Sol ™ were added to the standard coating solution as a swelling component for the production of coating suspensions. Coating suspensions were sprayed (Capsule Coater, Labo Tech) onto gelled capsules in an amount of 50 ± 5 mg of dry coating material per capsule. Capsules contained 50 mg of 5-ASA, Avicel and 5% Primojel ™. The size of the charge was 20 capsules. Following the coating step, the capsules were heated for 1 hour at 50 ° C. to evaporate the solvent mixture and obtain a polymer film, such as a composite coating layer was formed around the capsule.

Capsules were tested in the GISS described in Example 1 to study the release profile of 5-ASA from each batch of coated capsules.

Results.

Table 8 shows the results of measurements of the release made on capsules containing various amounts of Ac-Di-Sol. The table shows the total quantities of the drug during the test (Released), the time at which the release of the drug (T ₀ ), the time required to release 50% of the drug after the start of the release (T ₅₀ ), the time required to release 70 % drug (T ₇₀ ), and the percentage of release in the colon of the total released amount (CRP-TQR).

Table 8
Measurement results of drug release using Eudragit S100 based coatings containing different amounts of Ac-Di-Sol Released (%) T ₀ (min) T ₅₀ (min) T ₇₀ (min) CRP-TQR Ac-Di-Sol 0% 19 255 > 105 > 105 - Ac-Di-Sol 3% 94 246 eighteen 27 36 Ac-Di-Sol 5% 87 243 17 28 26

The results clearly show that incorporation of Ac-Di-Sol into the coating increases the pulsed release of the drug and increases the amount of drug delivered to the rectum.

Example 5

In another embodiment, an aqueous dispersion of the following composition:

Water
Eudragit s100
Ammonium (1 M)
Triethyl citrate
Primojel ™ 22.71 g
8.43 g
4.29 g
4.22 g
0.12 g

The dispersion quickly turned into a very viscous mass, which could not be sprayed onto tablets, capsules or pills. This means that the use of aqueous solvents is not suitable for the production of the systems described in this invention.

Claims (15)

1. A pH controlled pulsed release system (PPRS) comprising a core surrounded by an outer coating layer, wherein said core comprises an active ingredient, and wherein said outer coating layer comprises a pH sensitive coating material that includes a swellable component having the ability swell in water equal to at least 1.1 with respect to its own weight, wherein said swellable component is present in the above coating layer in an amount which, depending on the particle size and structures Coating forms a coating with a non-transmitting system. 2. The system according to claim 1, in which the specified swelling agent is capable of collecting water equal to at least 5, preferably at least 10 with respect to its own weight. 3. The system of claim 1 and 2, wherein the above swellable component is selected from the group consisting of sodium starch glycolate and cross-linked carboxymethyl cellulose, preferably wherein the above swellable component is starch glycolate sodium. 4. The system of claim 1, wherein the above swellable component is sodium starch glycolate. 5. The system of claim 1, wherein said coating material is selected from the group consisting of cellulose acetate trimelate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, co-polymerized methacrylic acid / methacrylic acid methyl esters, for example, materials known under the trade EUDRAGIT ™ brand. 6. The system of claim 1, wherein said coating layer further comprises a plasticizer. 7. The system according to claim 1, in which the specified active substance is a pharmaceutically active substance. 8. The system of claim 7, wherein said pharmaceutically active substance is selected from the group consisting of neurotransmitters, such as L-Dopa, agonists or antagonists of hormones, such as setrorelix, steroidal and non-steroidal anti-inflammatory drugs, stable isotopes, immunogenic substances, such like vaccines, or combinations thereof. 9. Coating suspension for use in the preparation of pH-controlled pulsed release systems (PPRS) according to claim 1, wherein said suspension comprises a mixture of a pH-sensitive coating material and a swelling agent in a solvent or a mixture of solvents in which said coating material is soluble in said solvent, and where the swelling agent is insoluble and does not swell in the specified solvent. 10. The coating suspension of claim 9, wherein said solvent or mixture of solvents contains an organic solvent. 11. A method of producing systems for pH-controlled pulsed release of a solid substrate, comprising the steps of obtaining a coating suspension according to claim 9 or 10, applying the above suspension to a solid substrate and evaporating the solvent from the suspension so that a coating layer is formed in which the swellable component is included in a matrix of pH-sensitive coating material. 12. The use of a coating suspension according to claim 9 or 10 to obtain pH-controlled pulsed delivery systems, preferably drug delivery systems. 13. A pharmaceutical composition comprising a pH controlled pulsed release system (PPRS) according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier. 14. A method for site-specific drug delivery, comprising administering a suitable amount of a pharmaceutical composition according to claim 13 to a subject in need thereof. 15. The method according to 14, in which the specified place-specific delivery includes the delivery of a medicinal substance directed to the colon or duodenum.

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