JP5134955B2 - Tablets having a part-time controlled gastrointestinal release action of active ingredients - Google Patents

Description

1. The present invention relates to pharmaceutical dosage forms having a site- and time-controlled gastrointestinal release action of the active ingredient.

2. Description of the Prior Art The release of non-steroidal anti-inflammatory drugs in the stomach frequently causes ulcers in the gastric mucosa. For this reason, tablets with a gastric juice-resistant coating are almost exclusively used at present. The disadvantage is that the active ingredient is often released very quickly at the entrance to the intestine. Therefore, using this technique, it is only possible to control the site of active ingredient release, but not the timing of release.

  Some active ingredients can only be absorbed at a specific location in the gastrointestinal tract. Active ingredient entry / migration into the plasma is often desired only when the pathological condition is particularly manifested at a specific time of day (circadian rhythm). For example, early morning asthma or ischemia, morning joint pain, etc. On the other hand, for some drugs, the effect of the drug is often only desired locally in the gastrointestinal tract, such as for inflammation (eg ulcerative colitis or Crohn's disease) or infection of the gastrointestinal tract.

  Coated tablets have often been described, particularly for the purpose of delayed release of the active ingredient, in which case the active ingredient is released from the tablet after an initial phase (lag phase) in which no active ingredient is released.

  For example, WO02 / 072033 describes that the amount of coating material applied determines the lag phase. The coating consists of a swellable material through which the active ingredient is released. In this case, diffusion through the swellable matrix of the coating is a determinant of release. However, the release through the pores often does not occur spontaneously after the desired lag phase, and conversely, there is a more or less rapid onset of release. Furthermore, the influence of food on the swelling and erosion of the coating is very significant.

  US Pat. No. 5,464,633 describes tablets for delayed release of active substances. The tablet consists of a core composed of the active ingredient and polymer and a polymer-containing coating.

  EP 0463877 describes a formulation for the controlled release of active ingredients, which consists of a core and a coating layer, which consists of a water-repellent salt and a copolymer.

  A formulation consisting of a multilayer coating for releasing the core and the active ingredient in the lower gastrointestinal tract (colon) is known, for example from EP 0366621. Film coatings that are degraded by bacteria present there only in the colon, however, are unsuitable for releasing the active ingredient in the upper intestine.

  WO 01/80824 (Eurand) describes a pharmaceutical dosage form having a core which also contains a hydrophilic swellable polymer in addition to the active ingredient and a surrounding coating consisting of at least one water insoluble polymer. .

  EP0939623B1 and US Pat. No. 6,183,780 (Duphar) describe oral dosage forms with a delayed release action consisting of a core and a coating, in which the coating is one or more polymers, water-soluble plasticizers and substances that increase the brittleness of the coating. Consists of. The disadvantage of this form is that it is particularly concerned about the effects of food.

  EP 1067910 (Bar-Shalom) describes an oral dosage form having at least one erodible surface. EP 1275381 (Yamanouchi) also describes a core tablet with a coating, which consists of a swellable hydrophilic polymer. In these cases, the influence of food is great.

  Administration of dilithiazem in the form of a biologically inert pellet with multiple layers is described in US6620439 (Elite Labs). In this case, the active ingredient is released several hours after ingestion to treat morning arterial occlusion.

  US Pat. No. 5,792,476 describes a pharmaceutical composition for oral administration for rheumatoid arthritis, which contains glucocorticoid as an active ingredient and is released in the small intestine. The composition is a granule laminated with an inner layer that is resistant to pH 6.8 and an outer layer that is resistant to pH 1.0.

  US Pat. No. 6,488,960 describes a pharmaceutical dosage form for controlled release of corticoylod with reference to the process described in US Pat. No. 5,792,476.

  WO 01/08421 describes a tablet coated with at least two layers, one of which is completely encapsulated by another layer. This coating layer can be produced by spray application and / or compression molding.

  WO 01/68056 discloses a formulation with a time-delayed release profile, which consists of a core and at least one hydrophilic or lipophilic coating surrounding the core, wherein the coating is in the release medium. Slowly swells, dissolves, erodes or changes its structure due to the water present in the core, allowing the core or part of the core to come into contact with the release medium. The coating can be shaped, for example, as a compression coating.

  WO 02/072034 describes a delayed release pharmaceutical dosage form having a core comprising glucocorticoid as an active ingredient and a substance comprising delayed release and comprising at least one natural or synthetic gum.

WO 2004/093843 discloses a tablet having a specific core shape for releasing the active ingredient in a specific delayed release method, which is incorporated herein by reference.
BRIEF SUMMARY OF THE INVENTION The problem underlying the present invention was to provide a pharmaceutical dosage form having a site- and time-controlled release action of the active ingredient, which is independent of the patient's food intake. In particular, it allows for in vivo release reproducible at the desired site. Furthermore, it has been a problem that the active ingredient release process itself can be controlled as optimally as possible based on appropriate medical instructions.

  This problem is solved by a pharmaceutical dosage form having a site- and time-controlled release action of the active ingredient, which is (a) having at least one active ingredient and when the core is in contact with the gastrointestinal fluid. A core having at least one swellable adjuvant such that the active ingredient is rapidly released from the dosage form; and (b) an inert coating compression molded onto the core, the coating comprising the agent Substantial release of the active ingredient can be suppressed for a period of time after taking the form.

  In another aspect, the invention relates to a method of treating a patient in need of treatment with an active ingredient in a site- and time-controlled dosage form, the method comprising the pharmaceutical dosage form described herein for said patient. Consisting of administering.

  In another aspect, the present invention relates to a kit comprising at least one dose formulation of a dosage form as described herein having a site- and time-controlled gastrointestinal release action of the active ingredient. The kit optionally includes directions for use of single dose formulations.

  In another aspect, the invention relates to a method of making a tablet that releases a corticosteroid active ingredient at various predetermined locations of the gastrointestinal tract, which method is desired to deliver the corticosteroid. A coated tablet having a core consisting of a corticosteroid and a swellable adjuvant and an inert outer coating; the coating of this tablet is selected to release the corticosteroid at the predetermined location Compression molding at a reduced pressure.

  In another aspect, the invention relates to a coated tablet having a corticosteroid active ingredient core and coating capable of releasing the corticosteroid at various predetermined locations in the gastrointestinal tract, the coating comprising the coating It is compression molded to the extent that corticosteroids are released at a predetermined location.

  In another aspect, the invention relates to a method of making a tablet that releases a corticosteroid active ingredient at various predetermined locations of the gastrointestinal tract, which method is desired to deliver the corticosteroid. A coated tablet with a core consisting of corticosteroid and swellable adjuvant and an inert outer coating, and the coating of this tablet was selected to release the corticosteroid at this predetermined location It consists of compression molding with pressure and testing the release characteristics in a test tube in an elution apparatus to ensure the release of the active ingredient with a specific lag time.

  In another aspect, the present invention relates to a method for the treatment of a local bowel disorder in the lower intestine, which comprises in a patient in need of treatment a corticosteroid active ingredient core and coating, wherein the coating is cortised in the lower intestine. It consists of administering a coated tablet that is compressed to the extent that results in the release of a costeroid.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 represents the in vitro release of a new tablet (“Prednisene TR”) containing 5 mg of prednisone having a lag phase of about 4 hours (500 ml water, paddle, USP).

  FIG. 2 shows (A) a standard “Prednisone IR” tablet with 5 mg prednisone (= immediate release) tablet (2 am ingestion), (B) a new “Prednisone TR” tablet with 5 mg prednisone, “half fast” (8 pm ingestion), (C) In vivo plasma concentration of prednisone after administration of a new “Prednisone TR” tablet with 5 mg prednisone, food ingested state (8 pm ingestion).

  FIG. 3 shows (A) a standard “Prednisone IR” tablet with 5 mg prednisone (2 am ingested), (B) a new “Prednisone TR” tablet with 5 mg prednisone, “half fasted” (8 pm ingested), (C) 5 mg prednisone. 1 represents the in vivo plasma concentration of prednisone after administration of a new “Prednisone TR” tablet with a food intake (8 pm ingestion).

  FIG. 4 represents the in vitro release of “Prednisone TR” tablets containing 5 mg prednisone with a lag phase of 6 hours (500 ml water, paddle, USP).

FIG. 5 represents the in vivo plasma concentration profile after prednisone tablet administration.
(1) "Prednise IR" standard tablet (8am ingestion)
(2) "Prednisone IR" standard tablet (2am ingestion)
(3) New “Prednisene TR” tablets (“semi-fast”) with a 6 hour lag phase (8 am ingestion)
(4) New “Prednisone TR” tablets with 6 hours lag phase (food intake completed) (8 am ingestion)
Detailed description of the invention Site- and time-related gastrointestinal release of the active ingredient can be distinguished in two advantageous embodiments:
(1) Release in the upper intestine with the following objectives:
-Avoiding instability of the active ingredient in contact with gastric juice,
-Side effects of active ingredient release in the stomach, eg avoidance of ulcers,
-Optimal site and timing of absorption of the active ingredient and entry into the plasma after active ingredient release in the upper part of the small intestine,
-Achieving systemic effects in the optimal time,
-Development of local effects in the upper intestine.
(2) Release in the lower intestine with the following objectives:
-Local and targeted gastrointestinal release of the active ingredient,
-Avoiding side effects due to the active ingredient after (undesirable) absorption has taken place.

  The common feature of the two embodiments is that the pharmaceutical effect is significantly increased and its side effects are reduced.

  The first advantageous embodiment therefore provides a pharmaceutical dosage form having an active ingredient release action in the upper intestine within a period of 2 to 6 hours. A second advantageous embodiment provides a pharmaceutical dosage form having a site- and time-controlled release action of the active ingredient in the lower intestine within a period of 6 to 10 hours after ingestion.

  The invention described herein allows the active ingredient or combination of active ingredients to be released at specific sites and / or specific times depending on the composition, shape and manufacturing conditions, thereby reducing side effects and ensuring optimal effectiveness. To a new timed release ("TR") dosage form.

  For example, experiments have already been performed using prednisone ("Prednisone TR") as a model substance and can be applied to other active ingredients such as corticosteroids with comparable properties.

  The novel “TR” dosage forms described herein are different from prior art formulations. Surprisingly, due to the specific shape of the compression-molded coating with inert adjuvants and precisely matched process parameters, a reproducible lag phase and subsequent rapid release of the active ingredient or combination of active ingredients (drug release phase) Proven.

  Since the inert coating initially suppresses the release of the active ingredient or active ingredient combination for a precisely defined time, no absorption can occur. The water present in the gastrointestinal tract slowly penetrates through the coating and reaches the core after a predetermined time due to compression molding pressure. The coating component does not cause swelling or erosion of the coating part. When reaching the core, the water penetrating through it is absorbed very rapidly by the hydrophilic component of the core, so that the core capacity increases significantly, so that the coating completely disintegrates and breaks down, and the active and active components Each combination is released very rapidly.

  A particularly advantageous embodiment of this compression-molded “TR” tablet is obtained when a pre-compressed core tablet is subsequently compressed in a multilayer tablet press into a compression-coated tablet.

The tablet coating consists of the following materials, for example, to obtain a delayed release profile:
-Polymers or copolymers such as acrylic acid, methacrylic acid (eg Eudragits or Crbopol),
-Cellulose derivatives, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose, cellulose acetate,
-Polyvinyl alcohol,
-Polyethylene glycol,
-Salts of higher fatty acids, short, medium or long chain saturated or unsaturated fatty acid esters of mono- or polyhydric alcohols. In particular, stearic acid triglycerides (for example Dynarsan) or glycerol behenate (for example Compritol) are used.

  In addition, other adjuvants can be added to these materials to allow the tablet coating to be compressed. Typically used here are fillers such as lactose, various starches, cellulose and calcium hydrogen phosphate. The glidant used is usually magnesium stearate, in exceptional cases talc and glycerol behenate. Often, a plasticizer, preferably a plasticizer from the group of polyethylene glycol, dibutyl phthalate, diethyl citrate or triacetin, is added to the coating material.

  In order to obtain an optimal release profile, the tablet core should also perform a specific function and exhibit specific properties. Thus, after the lag phase, when a typical disintegrant is added to the inner core, a rapid release profile is obtained, which is derived, for example, from the following groups: cellulose derivatives, starch derivatives, cross-linked polyvinyl pyrrolidone. For example, the use of a blowing agent resulting from a combination of a weak acid and a carbonate or bicarbonate can also promote rapid release. Tablet cores may, for example, additionally contain matrix or filler ingredients (eg lactose, cellulose derivatives, calcium hydrogen phosphate or other substances known from the literature) and lubricants or glidants (usually magnesium phosphate, in exceptional cases talc and behen. Acid glycerol).

  The size of the core tablet should preferably not exceed a diameter of 6 mm (preferably 5 mm). Otherwise, the compression-coated tablets will be too large for ingestion. Consequently, the dose of active ingredient is in the range of 0.1-50 mg, very particularly 1-20 mg.

  The in vitro release profile of the “TR” dosage form according to the invention is such that advantageously less than 5% of the active ingredient is released during the lag phase. After the start of the release phase, preferably ≧ 80%, particularly preferably ≧ 90% of the active ingredient is released within one hour. In vitro release is advantageously measured in water using a USP paddle elution model.

  The active ingredients used are preferably derived from the group of glucocorticoids, all exhibiting comparable physicochemical properties. Such include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortron, clopredonol, deflazacoat, triamcinolone and the corresponding salts and esters thereof. This is especially true for prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fluocortron, clopredonol and deflazacoat and the corresponding salts and esters thereof.

With the “TR” tablet in this case, the following combination of core and coating materials has proven to be particularly suitable for achieving time- and site-controlled release, eliminating pH and food effects:
The coating advantageously consists of:
A hydrophobic wax material having an HLB value of less than about 5, preferably about 2. Carnauba wax, paraffin, cetyl ester wax are advantageously used for this purpose. Glycerol behenate has proven particularly suitable. The use of about 20-60% in the coating, especially about 30-50%, has proven very advantageous;
Non-fatty hydrophobic fillers, such as calcium phosphate salts, such as dicalcium phosphate. The use of about 25-75%, especially about 40-60% of these fillers in the coating has proven very advantageous here;
-In addition, the tablet coating is advantageously a binder, for example polyvinylpyrrolidone (PVP), for example about 4-12%, in particular about 7-10%, in a special case about 0.1-2%, in special cases about It also consists of a glidant with a concentration of 0.5 to 1.5%, for example magnesium phosphate. Colloidal silicon dioxide can be used, for example, as a flow regulator, usually at a concentration of about 0.25 to 1%. In order to further differentiate the dose, a colorant, preferably an iron oxide pigment, can be added to the tablet coating at a concentration of about 0.001-1%.

The core tablet advantageously consists of:
Active ingredients or combinations of active ingredients from the group of glucocorticoids, preferably prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortron, clopredonol, deflazacoat and triamcinolone and the corresponding salts and esters thereof . The dose of active ingredient ranges from about 0.1 to 50 mg, very particularly about 1 to 20 mg;
-Furthermore, the core tablet advantageously comprises a filler, for example lactose, starch derivatives or cellulose derivatives. It is advantageous to use lactose. The filler is present, for example, at a concentration of about 50-90%, especially about 60-80%. In addition, there is a disintegrant, for example cross-linked PVP or sodium carboxymethylcellulose, for example at a concentration of about 10-20%. Further binders, such as PVP, for example at a concentration of about 2-10%, especially about 5.5-9% and lubricants, for example magnesium stearate, about 0.1-2%, in special cases about 0.5 It may be present at a concentration of ~ 1.5%. Colloidal silicon dioxide is usually used at a concentration of about 0.25 to 1% as a flow control agent. In addition, colorants, preferably iron oxide pigments, can be added at a concentration of about 0.01 to 1% in order to distinguish the core from the coating with the naked eye.

An advantageous feature of the pharmaceutical dosage form according to the present invention is that the in vitro release and in vivo release (by oral ingestion) of the active ingredient should not differ by more than about 1 hour, particularly preferably more than about 30 minutes. Furthermore, it is advantageous that the in vitro release is substantially independent of the pH of the release medium or / and additive in the release medium simulating a high fat and low fat diet, i.e. does not change by more than about ± 20%. is there. Furthermore, it is advantageous that in vivo release is substantially independent of food intake and the time to reach maximum plasma concentration (t _max ) does not change more than about ± 20%. The plasma concentration reached upon in vivo release is advantageously independent of gastrointestinal pH and food intake.

With in vivo release in the upper intestine, advantageously equivalent parameters, in particular the highest plasma concentration reached (C _max ) and / or the area under the plasma curve (AUC), are obtained for rapid release dosage forms. In particular, a C _max of at least about 70%, preferably at least about 80% of the C _{max of} the rapid release dosage form is advantageous, and an AUC that does not vary more than about ± 25% is advantageously achieved. The in vivo plasma concentration is much lower for release in the lower intestine, which is also substantially independent of gastrointestinal pH and food intake. Thus, the latter aspect of the present invention is particularly suitable for the treatment of local inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, where systemic action is not required. In contrast, the first described embodiment where absorption occurs in the upper intestine is for the treatment of painful joint inflammatory diseases where systemic effects are desired, such as rheumatoid arthritis, allergies and nocturnal severe asthma attacks. Particularly preferred.

  The manufacturing method of a tablet is performed under the normal conditions of the pharmaceutical industry. Thus, standard methods for producing core tablets are used, such as weighing, sieving, mixing, aqueous granulation in a high speed mixer, fluid bed drying of granules, mixing and compression. Similar methods are used to produce the coatings: weighing, sieving, mixing, aqueous granulation in a high speed mixer, fluid bed drying of the granules, mixing and compression into compressed coated tablets.

  Besides the composition, the shape of the compression-coated tablet is very important. This can only be achieved using a tablet machine for the production of compression-coated tablets, spray coating being unsuitable.

  The tablet side compression coating thickness to upper or lower ratio is advantageously about 2.2 to 2.6 mm (relative to the side edges): about 1.2 to 1.6 mm and about 1. 0 to 1.4 mm (with respect to the lower side of the tablet), particularly preferably about 2.35 to 2.45 mm: about 1.35 to 1.45 mm (upper side of the tablet) and about 1.15 to 1.25 mm (lower) Side). This shape results in tablets that are small enough to avoid swallowing problems.

  Thus, tablets having a hardness of about 60-90 N are obtained, as measured in the European Pharmacopoeia 4, 2.9.8.

  Timed release ("TR") of the active ingredient can be controlled by adjusting the compression force while applying the coating to the tablet core. Thus, the compressive force used to release in the upper intestine is preferably up to about 600 kg, particularly preferably about 250-600 kg, while the compressive force used to release the active ingredient in the lower intestine. Is preferably above about 600 kg, particularly preferably from about 600 to 800 kg.

  The pharmaceutical dosage form is particularly preferably in the form of a tablet, but the dosage form can also be produced as a capsule.

  Next, the present invention will be described in detail with reference to examples.

Examples Example 1: Composition of prescription core tablet:
Corticosteroid ¹ 1mg
Lactose 42.80mg
Povidone 4mg
Carboxymethylcellulose, Na 11mg
Iron oxide, red 0.3mg
Magnesium stearate 0.6mg
Silicon dioxide 0.3mg
Or corticosteroid ¹ 5mg
Lactose 38.80mg
Povidone 4mg
Carboxymethylcellulose, Na 11mg
Iron oxide, red 0.3mg
Magnesium stearate 0.6mg
Silicon dioxide 0.3mg
Or corticosteroid ¹ 10mg
Lactose 33.80mg
Povidone 4mg
Carboxymethylcellulose, Na 11mg
Iron oxide, red 0.3mg
Magnesium stearate 0.6mg
Silicon dioxide 0.3mg
Coating composition:
Calcium phosphate 50%
Glycerol behenate 40%
Iron oxide, yellow 0.1%
Magnesium stearate 1.0%
Silicon dioxide 0.5%
^A corticosteroid consisting of a group of substances comprising ¹ cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, flucortisone, fluocortron, clopredonol, deflazacoat, triamcinolone and the corresponding salts and esters thereof.

  The composition of the tablet ensures that the effects of food, pH and gastrointestinal motility have no effect and that the active ingredient is released very rapidly from the tablet after completion of the lag phase.

Example 2: Manufacturing method and in vitro release Due to the fixed tablet shape, the lag phase of active ingredient release is determined only by variously adjustable compression forces. In this case, prednisone was used as the active ingredient.

Thus, for example, an average pressure of 400 kg results in a lag phase of 4 hours for compression. Table 1 summarizes the lag phase as a function of compressive force:
Table 1: Dependence of lag phase [h] on average compression force [kg]

  The lag phase is measured by the USP paddle elution model at 100 ppm in water at a temperature of 37 ° C. FIG. 1 represents representative release behavior (batch G360).

  Surprisingly, the lag phase and drug release phase (time) are equivalent for different release media for this formulation with a constant shape and the same compression pressure. This is evident from Table 2 (batch: G360).

Table 2: Delayed Phase and Drug Release Phase [Time] of Novel “Predonisone TR” with Active Ingredient Prednisone in Different Release Media in Elution Release in Test Tube, 500 ml, Paddle, USP

  This surprising discovery is very important as it aims to achieve site- and time-controlled release without food effects.

In addition, further experiments were conducted on 1 mg and 5 mg tablets containing prednisone as the active ingredient in order to correlate the compression force with the lag phase. The results are summarized below:

  Surprisingly, there are some differences in the compression force required between different strength TR tablets. Therefore, testing the in vitro characteristics of each batch in the dissolution apparatus is advantageous to confirm active release at a specific lag time. This can be easily monitored by the color change of the elution medium. Color is released from the colored core tablet.

Example 3: In vivo release Surprisingly, the exact delay of prednisolone release could be confirmed in vivo as measured in vivo.

Pharmacokinetic studies have shown that the delay in active tube release in vitro is 4 hours, exactly the same as in vivo, and then the concentration rises very rapidly. The plasma concentration of prednisone that occurs after administration of the novel “Prednisone TR” is depicted in FIG. This is in excellent agreement with the in vitro release profile over time. Furthermore, the simultaneous intake of food is clearly found to have no effect in vivo, and an equivalent plasma concentration is found in the “half fasted” state. This is surprising because food normally affects gastrointestinal motility, pH, luminal metabolism, and usually interacts with the dosage form. The industry guide “Food Effect Bioavailability and Fed Bioequilibrium Studies” of the FDA, Department of Health of December 2002 states that the difference in reaching t _max is not clinically meaningful.

It is therefore very significant that the lag phase for this “PredniseTR” tablet in vitro was 4 hours, which was found in vivo with and without food. Furthermore, food clearly has no effect on either the highest plasma concentration reached (C _max ) or the area under the plasma curve (AUC). The time until maximum plasma concentration is achieved (t _max ) is also independent of food intake.

The difference in t _max between tablets compared to semi-fasted and concurrent food intake is up to ± 20% and is therefore not clinically significant.

  To demonstrate the effect of food on active ingredient release from the new “timed release” dosage form, Applicants conducted pharmacokinetic studies on 27 subjects. Three types were compared: evening (8pm) new “Prednisone TR” pills with standard dinner (food ingested), evening (8pm) new “Prednisone TR” tablets about 17:30 ingested light dinner Administration (semi-fasted state) and standard Prednise Immediate Release (Decortin, Merck, Germany) at night (2am). The study is randomized as a single dose administered in a crossover manner and therefore follows normal prescribed conditions.

The purpose of the kinetic study was to relate the new tablet “Prednisene TR” to “semi-fast” and “food fed state” with the standard “Prednisone IR” tablet (with rapid release of active ingredient), C _max and It was to obtain an equivalent plasma concentration profile for AUC. The novel tablets described herein with the active ingredient prednisone have demonstrated that comparable plasma concentration profiles can be obtained.

  Plasma samples were taken at 0.5 hour intervals and later at 1 hour intervals.

  The found prednisone plasma concentrations are illustrated in FIG. 2 and the main pharmacokinetic properties are summarized in Table 3.

ｔ_ｍａｘ及びｔ_ｌａｇ値は平均（範囲）である。その他の値は、ＡＮＯＶＡから得た幾何学的平均（９０％Ｃｌ）である。 Table 3: Pharmacokinetic parameters for prednisone after administration of a single dose of 5 mg prednisone as a “Prednisone IR” or “Prednisone TR” tablet in 27 healthy male volunteers

The t _max and t _lag values are average (range). The other values are the geometric mean (90% Cl) obtained from ANOVA.

^* : Probability associated with the hypothesis that there is no difference between prescriptions (excluding ANOVA, t _max and t _lag value Friedman test).

  With respect to prednisolone, a metabolite of prednisone, these results could also be confirmed after administration of the new “Prednisone TR”.

Therefore, it was also possible to represent the equivalence between C _max and AUC of the new “Prednisone TR” tablets “semi-fast” and “food intake” for prednisolone. Thus, the plasma concentration profile of the metabolite prednisolone is independent of food intake.

  Plasma samples for measuring prednisolone were taken at 0.5 hour intervals and later at 1 hour intervals.

  The plasma concentrations found for prednisolone are illustrated in FIG. 3 and the main pharmacokinetic properties are summarized in Table 4.

ｔ_ｍａｘ及びｔ_ｌａｇ値は平均（範囲）である。その他の値は、ＡＮＯＶＡから得た幾何学的平均（９０％Ｃｌ）である。 Table 4: Pharmacokinetic parameters for prednisolone after administration of a single dose of 5 mg prednisone as a “Prednisone IR” or “Prednisone TR” tablet in 27 healthy male volunteers

The t _max and t _lag values are average (range). The other values are the geometric mean (90% Cl) obtained from ANOVA.

^* : Probability associated with the hypothesis that there is no difference between prescriptions (excluding ANOVA, t _max and t _lag value Friedman test).

Typical reached C _max values for prednisone tablets 5 mg after ingestion range from about 15 to about 25 ng / ml, and prednisone AUC is about 75 to about 150 h ^* ng / mL. The achieved C _max value of the prednisolone metabolite ranges from about 100 to about 160 ng / ml, and the AUC of prednisolone is about 500 to about 700 h ^* ng / mL.

Furthermore, the coefficient of variation of C _max , t _max and AUC after administration of the standard tablet “Predniseone IR” (at 2 am) with and without food and the new tablet “Prednisene TR” (at 8 pm) should be approximately the same. I will add. This has not been described so far for modified release tablets of the active ingredient. Table 5 summarizes the prednisone coefficient of variation.

Table 5: C _max , t _max and AUC coefficient of variation of prednisone plasma concentration after administration of the “half-fasted” and “food fed” standard tablets “Prednisone IR” and the new tablet “Prednisone TR”

  The coefficient of variation of pharmacokinetic parameters for the metabolite prednisolone is also very slightly different when comparing standard and new tablets.

Table 6:
Factors of variation for C _max , t _max and AUC of prednisolone plasma concentrations after administration of the “half-fasted” and “food fed” standard tablets “Prednisone IR” and the new tablet “Prednisone TR”

  The situation is very different when administering tablets with a relatively long delayed phase (6 hours in vitro). Indeed, release after 6 hours was again observed in the test tube. At the same time, however, absorption is significantly reduced. This is because release is apparently in the lower intestine and absorption is only to a minor extent. This was demonstrated in a second pharmacokinetic study. FIG. 5 represents a new “Prednisone TR” with a 6 hour delay phase that can be manufactured using higher pressures for compression.

Typical ingested C _max values for such 5 mg prednisone tablets after ingestion range less than 15 ng / ml, and prednisone AUC is less than 75 h ^* ng / mL. The reached C _max values for prednisone metabolites range from less than 100 ng / ml, and the AUC for prednisone is less than 500 h ^* ng / mL.

  From this, a very advantageous new therapy is derived, and the present invention relates to this. Thus, the composition of the tablet, its specific shape and the compression force which can be adjusted in various ways allow the tablet coating to release the active ingredient from the core tablet very rapidly after a precisely defined time. This is very advantageous because the release site can also be accurately defined by this precise preconditioning.

  On the one hand, local lesions of the gastrointestinal tract can be locally treated by the release site. For example, ulcerative colitis and intestinal inflammatory disorders affect different parts of the intestine. This novel timed release ("TR") tablet is particularly advantageous for lower intestinal disorders. This is because the active ingredient is mainly locally released and its absorption is negligible or very limited. Thereby, the action that normally takes place after the active ingredient has been taken into the blood can be avoided.

  However, with a precisely controlled release after a precisely defined lag phase, a corresponding plasma concentration profile can also be obtained after administration of the rapid release tablet. However, this precondition is that the coating of the new timed release ("TR") tablet exposes the active ingredient-containing core after less than 6 hours, and then the active ingredient dissolves and is absorbed very quickly. . One such application is the administration of, for example, corticoids for the treatment of inflammatory diseases to the joints, where pro-inflammatory cytokines are released early in the morning, which causes morning pain and morning finger stiffness. Possible cause. This new tablet can now be ingested at 10 pm and released at 2 am, and thus described by Arvidson et al. (Annals of Rheumatomic Diseases 1997; 56: 27-31), ensuring the optimal effect of cortisone on rheumatoid arthritis. And can contribute to a dramatic increase in patient compliance. Thus, the tablet of the present invention can be taken once a day at bedtime, for example, between about 8 pm and about 12 am, more preferably between about 9 pm and about 11 pm.

  The present invention provides a method of making a tablet that releases corticosteroid active ingredients at various predetermined sites in the gastrointestinal tract, which defines: the site of the gastrointestinal tract where the corticosteroid needs to be delivered; A coated tablet having a core composed of a costeroid and a swellable adjuvant and an inert outer coating is produced; the tablet coating is compressed at a pressure selected to release the corticosteroid at the predetermined site: It consists of testing the in vitro release characteristics in an elution apparatus to confirm the release of the active ingredient with a characteristic lag time. Here, the in vitro release characteristics can be correlated to a suitable in vivo release lag time.

  In an advantageous embodiment, the tablet core consists of a colored material and the in vitro release of the active ingredient is measured by the color change. The elution device may be any industry standard device, preferably USP XXVIII.

FIG. 1 represents the in vitro release of a new tablet containing 5 mg of prednisone (“Prednisone TR”) with a lag phase of about 4 hours (500 ml water, paddle, USP). FIG. 2 shows (A) a standard “Prednisone IR” tablet with 5 mg prednisone (= immediate release) tablet (2 am ingestion), (B) a new “Prednisone TR” tablet with 5 mg prednisone, “half fast” (8 pm ingestion), (C) New “Prednisone TR” tablets with 5 mg prednisone, representing in vivo plasma concentration of prednisone after administration in a pre-fed state (8 pm ingestion) FIG. 3 shows (A) a standard “Prednisone IR” tablet with 5 mg prednisone (2 am ingested), (B) a new “Prednisone TR” tablet with 5 mg prednisone, “half fasted” (8 pm ingested), (C) 5 mg prednisone. New "Prednisene TR" tablet with, representing in vivo plasma concentration of prednisone after administration of food ingested state (8 pm ingestion) FIG. 4 represents the in vitro release of a “Prednisone TR” tablet containing 5 mg of prednisone with a lag phase of 6 hours (500 ml water, paddle, USP). FIG. 5 represents the in vivo plasma concentration profile after prednisone tablet administration

Claims (25)

Determining the site of the gastrointestinal tract where the corticosteroid needs to be delivered; producing a coated tablet having a core comprising a corticosteroid and a swellable adjuvant and a non-swellable and non-erodible inert outer coating; and look including compressing the selected pressure to release the corticosteroid coated tablets at sites defined in advance before said, this time, the coating, based on the total weight of the coating, the hydrophobic wax material 20 60%, non-fatty hydrophobic filler 25-75%, binder 4-12%, glidant 0.1-2%, flow modifier 0.25-1% and pigment 0-1% . A method of making tablets that releases corticosteroid active ingredients at various predetermined sites in the gastrointestinal tract.   The active ingredient is rapidly released when the core contacts the gastrointestinal fluid and the coating can inhibit substantial release of the active ingredient for a period of time after ingestion of the dosage form. Method.   The method of claim 1, wherein the active ingredient is effective in the treatment of local inflammatory bowel disease in the upper intestine.   The method of claim 1, wherein the active ingredient is effective in the treatment of local inflammatory bowel disease in the lower intestine.   The method according to claim 3 or 4, wherein the disease is selected from the group consisting of Crohn's disease and ulcerative colitis.   The method of claim 1, wherein the coating is produced with a compressive force of up to 600 kg.   The method of claim 1, wherein the coating is produced with a compressive force above 600 kg.   The method of claim 1, further comprising the step of testing in vitro release characteristics in an elution device to confirm release of the active ingredient at a specific lag time.   9. The method of claim 8, wherein the core comprises a colored material and the release of the active ingredient is measured by a color change. With a corticosteroid active ingredient and a swellable adjuvant core and a non-swellable and non-erodible inert outer coating, the corticosteroid can be released at various predetermined gastrointestinal tract sites, the earlier than tare compressed to such an extent that to release corticosteroids advance-determined site, in which the coating is, based on the total weight of the coating, the hydrophobic wax material 20% to 60%, non-greasy hydrophobic Coated tablet consisting of 25-75% filler, 4-12% binder, 0.1-2% glidant, 0.25-1% flow modifier and 0-1% pigment .   The tablet of claim 10, wherein the core further comprises a disintegrant.   11. A tablet according to claim 10, wherein the active ingredient is released in the upper intestine within a period of 2 to 6 hours after ingestion.   The tablet according to claim 10, wherein the active ingredient is released in the lower intestine within a period of 6 to 10 hours after ingestion.   The tablet according to claim 10, containing 5 mg of prednisone.   The tablet according to claim 10, wherein the active ingredient is effective for the treatment of local inflammatory bowel disease in the lower intestine.   16. A tablet according to claim 15, wherein the disease is selected from the group consisting of Crohn's disease and ulcerative colitis.   11. A tablet according to claim 10, wherein the coating is produced with a compression force greater than 600 kg.   The core is corticosteroid, filler 50 to 90%, disintegrant 10 to 20%, binder 2 to 10%, glidant 0.1 to 2%, flow modifier 0 relative to the total mass of the core. 11. A tablet according to claim 10 consisting of 25-1% and pigment 0-1%.   The filler is made of lactose, the disintegrant is made of cross-linked polyvinyl pyrrolidone, sodium carboxymethyl cellulose or a mixture thereof, the binder is made of non-cross-linked polyvinyl pyrrolidone, the lubricant is made of magnesium stearate, and the flow modifier is made of colloidal silicon dioxide. The tablet according to claim 18, wherein the pigment comprises iron oxide. 20. A tablet according to claim 19 , wherein the hydrophobic wax material comprises glycerol behenate and the non-fatty hydrophobic filler comprises calcium phosphate. 21. The tablet of claim 20 , wherein the non-fatty hydrophobic filler consists of dicalcium phosphate or basic calcium phosphate.   11. A tablet according to claim 10, wherein the active ingredient consists of one or more corticosteroids.   The group consisting of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortron, clopredonol, deflazacoat, triamcinolone and pharmaceutically acceptable salts and esters thereof and mixtures thereof The tablet according to claim 10, selected from: 24. A tablet according to claim 23 , wherein the active ingredient is selected from the group consisting of prednisone, prednisolone, methylprednisolone and budesonide.   The tablet according to claim 10, wherein the amount of the active ingredient is 0.1 to 20 mg.

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