JP2005528388A - Improved controlled release formulation - Google Patents

Abstract

A controlled release formulation having one or more coated core elements. Each core element contains an active ingredient and has a controlled release coating. Since a stabilizing coat is provided between each core element and its controlled release coating, the amount of active ingredient released at any point in the post-storage dissolution profile is determined at any point in the pre-storage dissolution profile during in vitro dissolution testing. Even within 40 percentage points of the amount of active ingredient released. The present invention also provides a method of administering an active ingredient that normally causes nausea and stomach irritation when administered in an immediate release form, which includes administering a controlled release preparation of the present invention.

Description

FIELD OF THE INVENTION This invention relates to improvements in controlled release formulations such as modified release pharmaceutical preparations.

Background Art Controlled release preparations provide an in vivo release profile ("controlled release") of an active ingredient, such as a pharmaceutical active ingredient, which differs from an uncontrolled in vivo release profile of the active ingredient ("immediate release") It is. Controlled release can be something like delayed, extended, pulsed or sustained release. Controlled release may be desired for several reasons, such as to minimize drug side effects or to reduce patient frequency and increase patient compliance.

  As with all pharmaceutical preparations, an important aspect of manufacturing controlled release preparations is their stability over an extended period of time, often referred to as “shelf life”. Typically, the shelf life of a preparation is related to two aspects, but the first is the stability of the component itself, ie the time of its chemical, microbiological, therapeutic and toxicological properties. The second is the maintenance over time of the rate intended at the beginning of drug release from the dosage form. The present invention is directed to this second stability aspect.

  Every pharmaceutical preparation must have a reasonable shelf life, which is the time that it can be guaranteed to have the same properties that it had when it was manufactured. These properties can be such as impurity content, pharmaceutical degradation, or rate of drug release. For oral preparations, this shelf life is usually at least 18 months.

  However, it has been found that in some controlled release preparations, this release profile changes by a significant amount after storage. For example, some delayed release preparations formulated with an enteric coating to release a very small amount (less than 10%) of the active ingredient after 20 minutes may contain 20 minutes after storage of the preparation. Up to 80% of the active ingredient can be released. This increase in release rate may impair the usefulness and effectiveness of the product.

  The object of the present invention is to provide a controlled release preparation which is stable in that the release profile after storage of the preparation according to the invention is substantially the same as the prerelease storage profile of the preparation. .

SUMMARY OF THE INVENTION The present invention provides a controlled release formulation having one or more coated core elements (each core element includes an active ingredient) and a controlled release coating. Here, a stabilizing coat is provided between each core element and its controlled release coating, so that the amount of active ingredient released at any point in the dissolution profile after storage is preserved during in vitro dissolution testing. Within 40 percent points of the amount of active ingredient released at any point in the pre-dissolution profile. (Parcentage points) "
In a preferred form, the amount of active ingredient released at the majority of the time points of the dissolution profile after storage is 30 (within a percentage point but less than the amount of active ingredient released at the same time point of the dissolution profile before storage). Preferably it is within 20 percentage points and more preferably within 10 percentage points.

  The term “percentage points” means the cumulative amount of active ingredient released. Thus, if the formulation releases 10% of the total active ingredient immediately after manufacture (represented by the pre-storage dissolution test referred to above), at the same point in the post-storage dissolution test, It releases 40% or less, more preferably 30% or less, and most preferably 20% or less of the amount.

  With respect to the expression “the majority of time points of the dissolution profile after storage”, one skilled in the art knows that certain preparations may have irregular spikes at several points in the profile for a variety of reasons. Will be understood. Indeed, at some point in time, the amount released can be outside the more preferred 30, 20, and 10 percentage point ranges. Preferably, such irregularities occur as isolated events for individual preparations, and preferably at time points that are not more important early dissolution times, such as the first 20 minutes after initiation. In fact, it should be understood that a post-storage dissolution profile that substantially meets the above requirements is considered to indicate a preparation within the scope of the present invention.

  Further reference to determining whether a preparation conforms to the present invention, the preparation is subjected to standardized storage tests based on accelerated storage conditions referenced in US Food and Drug Administration (FDA) guidelines. In vitro dissolution tests may be performed. This guideline stipulates accelerated conditions as storage of a medicinal product (ie, in its container and packaging) for 6 months at 75% relative humidity (RH) and 40 ° C. However, it has recently been proposed that suitable acceleration conditions for such pharmaceuticals would be 12 months storage at 60% RH and 30 ° C.

  The above set of conditions is considered equivalent for the purpose of in vitro dissolution tests that can be performed to determine if a preparation falls within the scope of the present invention. In fact, products that meet the above criteria after any of these storage conditions are considered to be within the scope of the present invention. However, the accelerated storage conditions described above represent preparations falling within the scope of the present invention, and the present invention also includes several such as in vitro dissolution tests following storage for extended periods (such as 24 months). It should be understood that preparations tested by other means are also included.

  Of course, in vitro dissolution tests should be performed to provide a dissolution profile that is a plot of the percentage of active ingredient released in a defined aqueous medium versus time. Such dissolution profiles can be measured utilizing a standard USP XXIV 2000-device 1 (basket).

  Controlled release preparations according to the present invention are typically such that provide a delayed release of the active ingredient with respect to the dissolution profile of the active ingredient. In this regard, if the controlled release is such that it provides a delayed release (commonly referred to as a “delayed release preparation”), the preparation delays the release of the active ingredient in the stomach and is caused by the release in the stomach. The aim is to minimize the side effects of possible active ingredients. These side effects include nausea and gastrointestinal irritation.

Most delayed release preparations are intended for the active ingredient to be released in the upper region of the small intestine for several reasons:
The active ingredient can begin to act as soon as possible after ingestion, without the side effects caused by the active ingredient released in the stomach;
• Conditions in the upper small intestine are usually optimal for absorption of active ingredients; and • Avoid acid degradation in the stomach of active ingredients.

  To explain, the stomach contents of a healthy person having an average meal usually have a storage time of 30 minutes to 1 hour and are usually in the stomach pH in the range of 1 to 3. The stomach contents then move to the intestine where the pH usually ranges from 4 to 7, where rapid release of the active ingredient is desired to allow for rapid and complete absorption of the active ingredient. There may be release of the active ingredient in the stomach after the lag period, if the retention time is longer or the gastric conditions are unusual, but the release is much slower than the immediate release preparation and nausea And very localized concentrations that cause irritation do not occur.

  Thus, with an ideal delayed release profile, little active ingredient is released at low gastric pH in approximately 20 minutes and then 100% active ingredient is 60 minutes when placed in an aqueous solution at pH 4 Released within. The realistic profile is about 1 after 20 minutes in an in vitro test because it is difficult to obtain a preparation that does not release the active ingredient in the stomach and releases all the active ingredient in the intestine. Less than 10% of the active ingredient will be released at a pH of .2 and after 60 minutes at least 90% of the active ingredient will be released at a pH of at least 5. In one preferred form of the invention, no more than 20% of the active ingredient is released by 20 minutes at a pH of about 1.2, and at least 80% of the active ingredient is released by 60 minutes at a pH of at least 5. For in vitro testing, the release profile can be determined at pH 1.2 using 0.6N hydrochloric acid solution and at pH 5.5 using 0.05M phosphate buffer.

  Such release profiles are preferred for certain pharmaceutically active ingredients such as antibiotics or active ingredients that can cause nausea and gastrointestinal irritation but have a narrow absorption window in the upper part of the intestinal tract. For example, bisphosphonates are known to cause gastrointestinal ulceration at high doses, opioid analgesics cause nausea, and very basic active ingredients are neutralized by the acidic conditions of the stomach and do not precipitate and are absorbed It has been known. In addition, other reactions can occur that cause the activity of the active ingredient to disappear.

  As mentioned above, an important aspect of the manufacture (and also regulatory review and approval) of all controlled release preparations, including delayed release preparations, is their stability over an extended period of time, especially the preparation of the preparation. Involved in its ability to provide a dissolution profile that is largely unaffected during its shelf life.

  In this regard, it has been found that the dissolution profile of the controlled release preparation according to the invention is not significantly affected even after storage. This provides a high degree of confidence that the desired release profile is still maintained until the expiration date when determining the expiration date of a pharmaceutical made from the present preparation. That also makes it possible to set an extended expiration date.

  By way of example, in a special delayed release preparation (in this example a doxycycline active ingredient), the amount of active ingredient released at various times can be as follows (pH 1. In vitro dissolution test before storage in solution 2):

  In this example, the preparation according to the invention desirably releases the amount of active ingredient in the following range (ie within 40 percentage points) after exposure to accelerated storage conditions (within pH 1.2) In vitro dissolution test after storage in solution):

  Most preferably in this example, the amount of active ingredient released after exposure to accelerated storage conditions (again in an in vitro dissolution test performed after storage in a pH 1.2 solution) desirably is: Range (ie, up to about 20 minutes and including time within 20 (but preferably 10) percentage points and thereafter within 30 (but also preferably 10) percentage points):

Controlled release preparations according to the present invention should thus meet various national regulations and approval requirements in relation to shelf life and stability.
DETAILED DESCRIPTION OF THE INVENTION A preferred dosage form for the controlled release formulation of the present invention is formulated from a plurality of cores. Each core is preferably one of the above-described coated core elements, which is the core element containing the active ingredient and having a controlled release coating, with a stabilizing coat between the core element and the controlled release coating .

  In one form, a plurality of such coated core elements may be provided in a capsule. In a more preferred form, a plurality of such coated core elements (or a plurality of suitably agglomerated coated core elements) may be compressed together with suitable conventional tablet excipients and provided as tablets. The dosage form can also be a single coated core element large enough to be called a tablet.

  Although suitable tablet excipients are known to those skilled in the art, the optimal formulation of tablets requires the need for content uniformity (ie, there are the same number of coated core elements in each tablet and hence the same amount). To ensure that the active ingredient is present in each tablet) and the amount of excipients required to protect the brittle coating of the controlled release coated core element.

  In this regard, if the number of coated core elements is too small, content uniformity problems may occur, and if the number of coated core elements is too large, the tablets that cushion the coated core elements during compression into tablets. Insufficient excipients can compromise the controlled release coating. Thus, the percentage of each coated core element in each tablet is ideally in the range of 20-40% by weight of the total dose weight (more preferably 25-35%, but most preferably about 30%).

  Those skilled in the art will recognize that when a tablet is formulated, it is necessary to include excipients to perform the functions of fillers, binders, disintegrants and lubricants with the active ingredient when the tablet is formulated. Will be recognized. In the present invention, the active ingredient is present in the form of a core element with a controlled release coating. In some cases, tablets may also contain other ingredients such as fragrances, colorants, and the like.

The range of materials suitable for use as fillers, disintegrants, binders and lubricants is well known to those skilled in the art.
In the final tablet formulation, the coated core element may be present in an amount of 5-50% (w / w) based on the total tablet weight. If the coated core element is below a level of about 5% (w / w) in the tablet formulation, efficacy problems may occur or the tablet may be too large to swallow. If the coated core element is higher than a level of about 50% (w / w) in a tablet formulation, the tablet may contain too much coated core element and insufficient binder and the core coating may be impaired. Or the coated core elements may stick together due to the compressive force required to form the tablet.

  Preferably, lactose, microcrystalline cellulose and / or starch are used as fillers in the tablets. The total amount of lactose, microcrystalline cellulose + starch present in the tablet may range between 50-95% (w / w), based on the total weight of the tablet. A suitable disintegrant for use in the tablets of the present invention is crospovidone, which may be present in the range of 0-15% (w / w) based on the total weight of the tablet. A suitable lubricant for use in the tablets of the present invention is magnesium stearate, which ranges between 0.1 and 1.0% (w / w) based on the total weight of the tablet. May be present.

  The core element provides the active ingredient. The active ingredients may be embedded within and through the core element and may or may not be combined with conventional excipients, additives and fillers. Alternatively, the active ingredient itself may be coated, for example, on inert beads to provide the core element. Preferably, each core element has a diameter in the range of 50 microns to 2000 microns prior to coating with the stabilizing coat and the controlled release coating. If a single core element is used, the size of the core element will preferably range from 5 mm to 20 mm.

  The core element may be formed by any suitable method. For example, the core element may be formed by spheronisation, extrusion, marumerisation, or rotor granulation onto a seed core. Preferably, the core element is formed by extrusion.

  It is understood that the core element may contain any suitable or required additives such as excipients, fillers, or other ingredients. Preferably, the composition of the core element is carefully determined to further increase the likelihood that the post-storage dissolution profile is acceptable to the pre-storage dissolution profile.

In one preferred form of the invention, the core element is formed by extrusion using an extrusion solution.
The material for extrusion to form the core element preferably contains active ingredients, binders, wicking agents, and lubricants.

  Preferably, the binder is microcrystalline cellulose, although any co-processed microcrystalline cellulose containing powdered cellulose or additives such as silica may be used. Preferably, the amount of binder used ranges between 8 and 45% by weight, based on the total weight of the core element.

  It is preferred to have a wicking agent or water transport modifier in the core formulation. The wicking agent allows water to be transported throughout the core element and serves to release all active ingredients present in the core element. Preferably, the wicking agent is selected from lactose, microcrystalline cellulose, starch or sorbitol. Most preferably, the wicking agent is lactose. Preferably, the wicking agent is present in an amount of 0 to 45% by weight, based on the total weight of the core element.

  In some cases, the core element may also include a lubricant, and several suitable lubricants are known to those skilled in the art. In a preferred form of the invention, the lubricant is selected from sodium lauryl sulfate or magnesium stearate. Preferably, the lubricant is present in an amount ranging from 0 to 10% by weight, based on the total weight of the core element.

The active ingredient may be present in any suitable amount in the core element, eg it may be provided in an amount of 5 to 95% by weight, preferably 20 to 80% by weight, based on the total weight of the core element.
Those skilled in the art of making core elements as described herein are aware of other materials that can be used to provide the same physical effect as a binder, wicking agent or lubricant.

  The active ingredient may be any suitable and desirable drug, pharmaceutical or chemical. For example, the active ingredient may be doxycycline, tetracycline, oxytetracycline, minocycline, chlortetracycline, or demeclocycline acid salt. Any active ingredient that causes nausea or irritation but has a narrow absorption zone in the upper intestine will benefit from the application of the present invention.

The stabilization coat is a physical barrier between the active ingredient and the controlled release coating. The stabilizing coat is sometimes called a seal coat or an intermediate layer.
The purpose of the stabilizing coat is to separate the active ingredient and the controlled release coating. In this regard, the stabilizing coat is believed to delay the movement of moisture or solvent between the controlled release coating and the active ingredient. The stabilized coat preferably keeps the active ingredient separated from the controlled release coating during storage, but the stabilized coat ideally does not significantly interfere with the release rate of the active ingredient, It should therefore be at least semi-permeable in an aqueous medium and may be soluble. In fact, the stabilizing coat is intended to keep core material movement to a minimum so as to allow release of the core material in an aqueous environment while suppressing or preventing its interaction with the coating material. .

  The stabilizing coat may be any suitable material that provides an inert barrier between the core element or active ingredient-containing layer and the controlled release coating, and may be a water-soluble, water-swellable, or water-permeable polymer or monomer material. possible. Examples of such materials include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, or methacrylate-based polymers (eg, Eudragit® RS or Eudragit® RL). .

  Preferably, the stabilizing coat includes a water soluble polymer that does not interfere with the release of the active ingredient and another agent that performs the same function as talc or talc. The water-soluble polymer and talc may be present in the range of the ratio of talc 1 to polymer 9 to the ratio of talc 9 to polymer 1.

  The controlled release coating can be any suitable coating material or combination of coating materials that provides the desired controlled release profile. For example, a coating such as an enteric coating, a semi-enteric coating, a delayed release coating, or a pulsed release coating may be desired. In particular, the coating would be suitable if it provided a suitable lag in active ingredient release prior to rapid release at a rate essentially equivalent to immediate release of the active ingredient.

  In particular, various grades of hydroxypropyl methyl phthalate (also as an aqueous dispersant), methacrylate based polymers (eg, Eudragit® L100-55 and Eudragit® L30D), and hydroxypropyl methylcellulose acetate succinate Any of these materials is suitable. It is also possible to use a mixture of enteric polymers to produce a controlled release coating. It is also possible to use mixtures of water-permeable, water-swellable or water-soluble materials and enteric polymers.

  Suitable water soluble or water permeable materials include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyethylene glycol or mixtures thereof.

  The controlled release coating is between 40-90% (w / w) enteric polymer and between 10-60% (w / w) water-soluble or water permeable based on the total weight of the controlled release coating. Material may be included. The controlled release coating may also contain 0-30% (w / w) plasticizer based on the total weight of the controlled release coating.

  The polymer coat weight of the controlled release coating (as a percentage of the total core) will vary depending on the desired delay and the polymer used, but is generally 5% (w / w) and 30% (w / w) ). The polymer coat weight means a polymer and a plasticizer in the coating layer, and does not include an additive such as talc.

  The stabilizing coat and controlled release coating may be applied to the core element to shape the coated core element in any suitable manner, such as by fluid bed coating and rotacoating including a wurster coating.

  Stability can be further improved by drying the core using any one of several drying techniques known in the art, such as oven drying or fluid bed apparatus drying.

Detailed Description of the Preferred Embodiments The invention will now be described with reference to several examples which illustrate preferred embodiments. However, the following description of the examples does not limit the generality of the above description.

In these examples:
Examples 1 and 2 illustrate a first preferred embodiment of the preparation according to the invention, Example 1 is directed to the core element, and Example 2 is directed to a tablet molded from this core element. There is supporting data illustrating the improved stability of the preparation.

Example 3 illustrates the core element of Example 1 after being subjected to a drying process and also provides supporting data illustrating improved stability.
Example 4 illustrates a second preferred embodiment of the preparation according to the invention and is directed to a tablet molded from the core element, which preparation is also expected to provide improved stability; and
Comparative Example 1 illustrates a third preferred embodiment of the preparation according to the invention, comparing comparative data on the stability of tablets containing a coated core element with a stabilizing coat to those without a stabilizing coat. Compared to offer.

Example 1
Core element manufacturing method

The core element is formed in a wet granulation process using a saturated solution of sodium chloride and in a high shear mixer.
The mixture is then extruded using a sieve size between 0.4 mm and 1.5 mm. The extrudate is then marumerised to produce a circular core element. The core element is dried in a fluid bed or oven.

Application of the stabilization coat The stabilization coat is applied to the core element using a fluid bed coating process. The stabilizing coat consists of a 2: 1 mixture of hydroxypropyl methylcellulose and talc. The target polymer coat weight (without talc, the weight of the polymer alone) is between 3% and 5% of the total weight of the core element and stabilizing coat. The polymer coat weight will vary depending on several factors such as the efficiency of the coating process, the batch of raw materials, and the like.

Application of controlled release coating

  Using a fluidized bed coating process, a controlled release coating is applied to the stabilized coated core element to shape the coated core element. The target polymer coat weight is 15% of the total weight of the coated core element.

  The in vitro release of this coated core element was tested using USP XXIV 2000-equipment 1 (basket) and the resulting dissolution profile (referred to as “initial” before storage) was dissolved after various storage times ( 1 month to 6 months).

  The following table shows the raw data of FIG. 1, from which the change in the amount of active ingredient released at most time points is less than 10 percentage points after 6 months of storage under accelerated conditions, It can be seen that the time point is less than 20 percentage points. It can also be seen that during the more important early period up to 20 minutes, the change in the amount of active ingredient released is within a smaller range.

Example 2
The coated core element prepared in Example 1 was formulated into a tablet.
Tablet formulation

The ingredients were combined in a tumble blender and then tableted using a rotary tablet press.
The tablet was tested for in vitro release using USP XXIV 2000-Apparatus 1 (basket) and the resulting dissolution profile (referred to as “initial” before storage) was varied with various post-storage dissolution profiles (1-6 months). 2) and FIG.

  The table below shows the raw data for the graph of FIG. 2, from which the change in the amount of active ingredient released at most time points is less than 30 percentage points after 6 months of storage under accelerated conditions ( And in practice, it is found to be less than 10 percentage points at most) and less than 40 percentage points at all time points. It can also be seen that during a more important early period up to 20 minutes, the change in the amount of active ingredient released is within a smaller range of 30 percentage points.

Example 3
The coated core element of Example 1 was additionally dried in an oven for 5 days at 50 ° C. prior to storage, and in vitro dissolution provided the dissolution profile before and after storage as shown in FIG.

Example 4
Preparation of the core element The core element is shaped using a wet granulation technique with a solution that is a saturated solution of sodium chloride. The core element is extruded to be between 0.4 mm and 1.5 mm in diameter. These are then malmized and dried to provide a formulation of the core element.

  Once the core elements are dry, they are coated with a stabilizing coat as follows using a fluidized bed. Once the stabilization coat has dried, the fluidized bed process is again used to coat the coated core element with a controlled release coat as follows. The complete coated core element is then tableted with a tableting excipient as described below.

Stabilization coat

Controlled release coat

Tablet preparation

Compress the above ingredients into an oval tablet. There is no secant or film coating. The final tablet weight is approximately 700 mg.
Comparative Example 1
An in vitro dissolution test of a “tablet” containing a coated core element with and without a stabilizing coat resulted in the comparative dissolution profile shown in FIG.

  The coated core element was molded according to the method described in Example 4 except that the extrusion solution was water. The coated core element had the following formulation:

  This coated core element was then tableted as in Example 2 to provide tablets of the following composition.

The tablets were stored for 12 weeks in a controlled environment at a temperature of 40 ° C. and 75% relative humidity, and the in vitro dissolution characteristics of the two tablet formulations were measured.
The following table provides comparative raw data for the graph of FIG. 4 and shows the percent release at 20 minutes for tablets containing coated core elements with and without stabilizing coat.

  Finally, there can be other changes and modifications to the preparations and methods described herein, which are also within the scope of the invention.

As part of the above description of the preferred embodiments, various drawings are provided in conjunction with the specification. In these drawings:
FIG. 1 illustrates the release rate of the active ingredient of the “core” of Example 1 immediately after manufacture and after various storage periods. FIG. 2 illustrates the release rate of the active ingredient of the “tablet” containing the core of Example 1 immediately after manufacture and after various storage periods. FIG. 3 illustrates the release rate of the active ingredient of the “dry core” of Example 1 immediately after manufacture and after various storage periods. FIG. 4 shows the comparative active ingredient release at 20 minutes of Comparative Example 1 “tablets with and without stabilizing coat” immediately after manufacture and after various storage periods. Illustrate.

Claims (28)

  A controlled release formulation having one or more coated core elements, each core element containing an active ingredient and having a controlled release coating, wherein a stabilizing coat is provided for each core element Active ingredient released at any point in the pre-storage dissolution profile at any point in the pre-storage dissolution profile during the in vitro dissolution test The preparation is within 40 percentage points of the amount.   The preparation according to claim 1, wherein the amount of active ingredient released at the majority of the time points of the dissolution profile after storage is also within 30 percentage points of the amount of active ingredient released at the same time of the dissolution profile before storage. Stuff.   The preparation according to claim 1, wherein the amount of active ingredient released at the majority of the time points of the dissolution profile after storage is also within 20 percentage points of the amount of active ingredient released at the same time of the dissolution profile before storage. Stuff.   The preparation according to claim 1, wherein the amount of active ingredient released at the majority of time points of the dissolution profile after storage is also within 10 percentage points of the amount of active ingredient released at the same time point of the dissolution profile before storage. Stuff.   5. A preparation according to any one of claims 1 to 4, wherein the controlled release coating is a delayed release coating.   Controlled release coatings release in vitro dissolution before storage at less than 20% active ingredient by 20 minutes at a pH of about 1.2 and at least 80% active ingredient by 60 minutes at a pH of at least 5 6. The preparation of claim 5, which is a delayed release coating suitable for   The controlled release coating releases in vitro dissolution prior to storage at 10% active ingredient by 20 minutes at a pH of about 1.2 and at least 90% active ingredient by 60 minutes at a pH of at least 5. 6. A preparation according to claim 5, which is a suitable delayed release coating.   The controlled release coating is an enteric coating, a semi-enteric coating, a delayed release coating, a pulse release coating, a mixture of enteric polymers, or a mixture of water permeable, water swellable or water soluble materials and enteric polymers. The preparation according to any one of claims 1 to 4.   The preparation according to claim 8, wherein the water-soluble or water-permeable material is one or a mixture of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyethylene glycol.   9. The preparation of claim 8, wherein the controlled release coating comprises one or more of hydroxypropyl methylcellulose phthalate, Eudragit L100-55, Eudragit L30D, or hydroxypropyl methylcellulose acetate succinate.   11. A preparation according to any one of the preceding claims, wherein the stabilizing coat is at least semipermeable in an aqueous medium.   12. A preparation according to claim 11, wherein the stabilizing coat is one or a mixture of water-soluble, water-swellable or water-permeable polymer or monomer materials.   13. A preparation according to claim 12, wherein the stabilizing coat is one or a mixture of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, Eudragit RS or Eudragit RL.   14. A preparation according to any one of the preceding claims, wherein the active ingredient is selected from the group comprising doxycycline, tetracycline, oxytetracycline, minocycline, chlortetracycline or demeclocycline acid salt.   15. A preparation according to any one of the preceding claims provided as a plurality of coated core elements in a capsule.   15. A preparation according to any one of the preceding claims, provided as a plurality of coated core elements that are compressed into tablets.   17. A preparation according to claim 16, wherein the percentage of coated core element in each tablet is in the range of 20-40% by weight of the total dose weight.   17. A preparation according to claim 16, wherein the percentage of coated core element in each tablet is in the range of 25-35% by weight of the total dose weight.   17. A preparation according to claim 16, wherein the percentage of coated core element in each tablet is about 30% by weight of the total dose weight.   The preparation of claim 1, wherein the controlled release coating is a delayed release coating, the active ingredient is doxycycline acid salt, and is provided as a plurality of coated core elements that are compressed into tablets.   A tablet for oral administration, which is a controlled release preparation having one or more coated core elements, each core element comprising an active ingredient and having a controlled release coating, wherein a stabilizing coat is provided for each core element The amount of active ingredient released at any point in the pre-storage dissolution profile during the in vitro dissolution test. Said tablet being within 40 percentage points of the quantity.   The tablet according to claim 21, wherein the controlled release coating is a delayed release coating and the active ingredient is doxycycline acid salt.   A core for use in a dosage form for oral administration, which is a controlled release preparation having one or more coated core elements, each core element comprising an active ingredient and having a controlled release coating, where it is stabilized A coat is provided between each core element and its controlled release coating so that during in vitro dissolution testing, the amount of active ingredient released at any point in the post-storage dissolution profile is determined at any point in the pre-storage dissolution profile. Said core being within 40 percentage points of the amount of active ingredient released.   24. The core of claim 23, wherein the controlled release coating is a delayed release coating and the active ingredient is doxycycline acid salt.   A method of administering an active ingredient that normally causes nausea and stomach irritation upon administration in an immediate release form, comprising administering a controlled release preparation according to claim 1.   26. The method of claim 25, wherein the controlled release coating is a delayed release coating and the active ingredient is doxycycline acid salt.   2. A controlled release preparation according to claim 1, substantially as described above with respect to the accompanying examples. A controlled release preparation as claimed in claim 1 and having a release profile substantially as described above with reference to the accompanying drawings.

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