KR100631873B1 - Alendronic Acid Formulations with Enhanced Bioavailability - Google Patents

Abstract

The present invention relates to an alendronic acid preparation having enhanced bioavailability, and more particularly, an alendronic acid or a salt thereof is contained as an active ingredient, and an absorption increasing agent and an absorption increasing auxiliary agent are included therein to increase each other. By increasing the bioavailability of the active ingredient by the action of the present invention relates to an alendronic acid preparation with enhanced bioavailability that can be expected to treat and prevent excellent osteoporosis.

Alendronic acid, osteoporosis

Description

Medicines of alendronic acid having improved bioavailability             

Figure 1 is a graph showing the effect of increasing the bioavailability of the alendronic acid or salts thereof by the synergistic action of the absorption increaser and the absorption enhancer.

The present invention relates to a preparation of alendronic acid with enhanced bioavailability, and more particularly, contains an alendronic acid or a salt thereof as an active ingredient and a complex forming material as an absorption increasing agent and an absorption increasing aid. The present invention relates to an alendronic acid preparation having enhanced bioavailability which can be expected to have an excellent therapeutic and prophylactic effect of osteoporosis by increasing the bioavailability of the active ingredient by synergistic interaction with each other.

It is well known that bisphosphonate compounds represented by Alendronic acid are effective for treating and preventing osteoporosis.

However, the preparation of alendronic acid has a very low bioavailability in the gastrointestinal tract, so it is recommended to take it on an empty stomach and fast after 30 minutes, which causes a lot of inconvenience. In addition, the preparation of alendronic acid has side effects on the gastrointestinal tract, such as esophagitis and gastritis, and should not be taken before bedtime or before waking up. Do not lie down for more than 30 minutes and after your first meal. In addition, it is recommended to take alendronic acid with water because ingestion of other beverages, including mineral water, food, and drugs may reduce absorption of the drug. This is because the alendronic acid or its salt has a strong affinity with divalent or higher metal ions such as calcium ions (Ca ²⁺ ) in the gastrointestinal tract and forms a poorly soluble substance by combining with these metal ions. When taken after meals or at the same time when taken with calcium, poorly soluble substances are formed in the digestive tract, and the absorption of alendronic acid or its salts in the digestive tract significantly decreases.

As a treatment method for reducing the side effects in the gastrointestinal tract of the alendronic acid preparation, instead of the 'continuous treatment' in which the drug is continuously taken daily, a 'periodic treatment' in which the drug is periodically taken for a certain period of time has been proposed. As an example, US Pat. No. 5,994,329 shows that conventional continuous therapy replaces once-daily, twice-weekly, once-weekly, or once-in-a-week instead of taking 10 mg of alendronic acid or its salts once a day. It has been suggested to take a regular dose cycle twice a month and take it according to a continuous schedule, but increase the unit dose to 70 mg once. This method only increases the single dose and decreases the number of doses, thereby ensuring a recovery period for the gastrointestinal tract injured due to the use of the preparation of alendronic acid. The risk of developing gastrointestinal side effects still persists. In addition, US Pat. No. 5,431,920 discloses enteric coating techniques for reducing gastrointestinal side effects of bisphosphonate compounds.

The above-mentioned prior arts have been developed to reduce gastrointestinal damage caused by oral administration of an alendronic acid preparation, and no consideration has been given to improving bioavailability for alendronic acid or salts thereof.

Prior art related to the improvement of bioavailability in the gastrointestinal tract of alendronic acid preparations is as follows. U.S. Patent No. 4,980,171 discloses a pharmaceutical composition containing 1.5 to 6% by weight of sodium lauryl sulfate in a bisphosphonate compound represented by alendronic acid to increase the absorption of the bisphosphonate compound. Also, jay. H. Lin (JH Lin) through the experiments using rats, using the EDTA, to suppress the formation of a sparingly soluble substance by binding to the calcium ions in vivo, and widening the intercellular gap in the upper part of the intestine Allen Increased uptake of dronic acid. Bon Vol. 18, No. 2, February 1996; 75-85] In addition, International Publication No. WO98 / 14196 has developed an alendronic acid solution containing citric acid and tartaric acid as a buffer system. In comparison, the bioavailability tends to increase. In addition, WO02 / 05786 discloses an effect of improving absorption in the mucous layer and mucosa of the digestive tract for various drugs including bisphosphonate compounds by uniformly combining aminoalkyl methacrylate copolymer E with an acidic substance. The digestive tract was defined as the small intestine and colon, consisting of the duodenum, jejunum and ileum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, except for the stomach. However, the present invention is applied not only to the bisphosphonate compound but also to various drugs, and no consideration is given to the absorption site of the bisphosphonate compound.

Prior arts related to improving bioavailability described above describe the absorption of alendronic acid or its salts in the upper intestine and vaguely in the gastrointestinal tract and in the digestive tract except the stomach. It is not intended to recognize and target bioavailability improvements.

The present invention is the result of a research effort to develop a novel alendronic acid formulations that can improve the disadvantages such as low bioavailability and side effects of the gastrointestinal tract of allendronic acid or salts thereof.

In other words, the present invention recognizes that in order to develop an oral administration of alendronic acid with enhanced bioavailability, it is necessary to accurately identify a site of significant absorption increase in vivo of alendronic acid or a salt thereof. It was completed by confirming the importance of targeting the stomach in the gastrointestinal tract as a site for increased absorption of the salt thereof. In the prior art related to alendronic acid preparations that have improved bioavailability known to date, these results are merely studies without accurate recognition and purpose of the importance of stomach as a site for increased absorption.

In addition, the present invention has been studied for the development of a formulation that can increase the absorption of the alendronic acid or salts thereof in the gastrointestinal tract, as a result of the absorption and absorption enhancer of a specific composition in the alendronic acid or salts thereof It was completed by developing a new formulation of alendronic acid, which contains a complexing substance and further enhances the bioavailability of the active ingredient by synergistic interaction with each other.

In addition, the present invention exhibited the same treatment and prophylaxis as osteoporosis when the new composition of the alendronic acid formulations are taken regularly, even if taking a certain period of administration every day, and the single dose in the conventional periodic therapy This can be achieved by reducing the risk of side effects of the gastrointestinal tract, which can be greatly reduced.

Accordingly, it is an object of the present invention to provide an allandronic acid formulation composition for treating and preventing osteoporosis, which can reduce the single dose when continuous administration is performed at regular intervals by a periodic treatment by enhancing bioavailability for alendronic acid or salts thereof. It is.

It is another object of the present invention to provide an alendronic acid formulation which is formulated to be administered at a specific single dose and cycle.

The present invention is characterized in that alendronic acid composition for treating and preventing osteoporosis, which comprises a complexing material as an alendronic acid or a salt thereof, an absorption enhancer, and an absorption enhancer.

In addition, the present invention comprises an alendronic acid formulation which is composed of the above-described composition and is formulated to be periodically taken in a single dose of less than 70 mg based on the active ingredient.

Referring to the present invention in more detail as follows.

The present invention relates to an oral dosage form of alendronic acid preparation composition which contains a complexing agent as an absorption enhancer together with an absorption enhancer in a composition containing an alendronic acid or a salt thereof as an active ingredient, and enhances the bioavailability of the active ingredient, It relates to an alendronic acid formulation formulated to be taken periodically at a dose of less than 70 mg.

Alendronic acid preparations according to the present invention are administered orally by reducing the dose once, according to a continuous schedule once a week, twice a week, two weeks, three weeks, or four weeks. . Alendronic acid 37 mg preparation according to the present invention shows bioavailability equivalent to that of 70 mg commercially available tablets once a week when administered orally. [Example 4 or Table 5] Therefore, the alendronic acid formulation of the present invention is applied to a periodic therapy for administering drugs at regular dose intervals, and thus shows an excellent osteoporosis treatment and prevention effect, so it is pointed out as a disadvantage in conventional daily continuous therapy. It can relieve side effects caused by gastrointestinal irritation. In addition, the alendronic acid formulation of the present invention has excellent bioavailability, thereby reducing the dose that can be caused by a single overdose by reducing the single dose in periodic therapy.

The composition of each of the ingredients for constituting the alendronic acid preparation according to the present invention will be described in more detail as follows.

In the present invention, the active ingredient contains alendronic acid or a salt thereof. In this case, the salts are pharmaceutically acceptable conventional salts well known in the art, and the present invention does not particularly limit the kinds of these salts.

In the present invention, a substance capable of increasing the absorption rate of the alendronic acid or a salt thereof in the gastrointestinal tract among the gastrointestinal tract is selected and used as an increase in absorption. When the absorption enhancer is used a substance exhibiting the permeability of the gastric mucosa and mucus layer, the absorption of the active ingredient in the gastric region can be further enhanced. More specifically, examples of the absorption increaser used in the present invention include polyoxyethylene mono- and / or di-fatty acid esters; Polyoxyethylene glycerol fatty acid esters; Transesterified compounds of alcohols and fatty acids; Polyglycerol esters of fatty acids; Propylene glycol fatty acid esters; Mono- and / or diglycerides of fatty acids; Sterols or sterol derivatives; Polyoxyethylene-sorbitan-fatty acid esters; Polyoxyethylene alkyl esters; Esters of sugars and fatty acids; Polyoxyethylene alkyl phenols; Polyoxyethylene polyoxypropylene copolymers or block copolymers; Sorbitan fatty acid esters; Fatty acids or fatty acid derivatives or salts thereof such as capric acid, sodium caprate, sodium lauryl sulfate; Bile acids or bile acid derivatives or salts thereof; Phospholipids such as lecithin; Secondary, tertiary, quaternary ammoniums or salts thereof; Fatty acid carnitines; Betaines; Docusate or salts thereof; 23-lauryl ether; Salicylic acid or salts thereof; Aprotinin; Laurocapram; Cyclodextrins; Methoxysalicylate; Dextran or a salt thereof; menthol; Sulfoxides; Alkyl glycosides; And mixtures thereof. In the absorption increasing agent used in the present invention, polyoxyethylene-sorbitan-fatty acid esters are preferred; Fatty acids or fatty acid derivatives selected from capric acid, sodium caprate, and sodium lauryl sulfate or salts thereof; Bile acids or bile acid derivatives or salts thereof; lecithin; Secondary, tertiary, quaternary ammoniums or salts thereof; Docusate or salts thereof; 23-lauryl ether; Salicylic acid or salts thereof; Aprotinin; Laurocapram; Cyclodextrins; Methoxysalicylate; Dextran or a salt thereof; menthol; Sulfoxides; Alkyl glycosides; And a mixture thereof. In addition, particularly preferred for the absorption increaser used in the present invention are polyoxyethylene-sorbitan-fatty acid esters; Fatty acids or fatty acid derivatives or salts thereof such as capric acid, sodium caprate, sodium lauryl sulfate; Bile acids or bile acid derivatives or salts thereof; Secondary, tertiary, quaternary ammoniums or salts thereof; Docusate or salts thereof; Laurocapram; And a mixture thereof.

In the present invention, a complex-forming material that forms a complex by combining with a metal ion as an absorption increasing auxiliary agent has its characteristics. Although there have been examples of prior arts using complex forming materials such as EDTA for the purpose of suppressing the formation of poorly soluble materials by incorporating alendronic acid into metal ions in vivo, the permeability of the gastric mucosa and mucous layer as in the present invention. The use of the complexing material as an absorption enhancer of the above-mentioned absorption enhancer in promoting the absorption of the alendronic acid or its salts in the stomach due to the use of this excellent absorption enhancer is not known until now. That is, the complex forming material to be used as the absorption increasing aid in the present invention has a slight effect of enhancing the absorption of the alendronic acid or salts thereof. However, in the present invention, when used together with an absorption increasing agent used for the purpose of enhancing the absorption of alendronic acid or a salt thereof in the stomach region, these interactions show a marked synergistic effect on enhancing bioavailability. Such absorption enhancers specifically include EDTA or salts thereof; EGTA or salts thereof; Citric acid or salts thereof; Phthalic acid or salts thereof; Malic acid or salts thereof; Maltol or salts thereof; Tartaric acid or salts thereof; Fumaric acid or salts thereof; Ethylenediamine; Porphine; Chlorophyll; And dimercaprol and the like. In the absorption increase aid used in the present invention, preferably, EDTA or a salt thereof; EGTA or salts thereof; Citric acid or salts thereof; Malic acid or salts thereof; Maltol or salts thereof; Fumaric acid or salts thereof; Ethylenediamine; And a mixture thereof. In addition, particularly preferred in the absorption increase aid used in the present invention is EDTA or a salt thereof; EGTA or salts thereof; Citric acid or salts thereof; Malic acid or salts thereof; And a mixture thereof.

Alendronic acid formulation composition of the present invention, based on a single unit dose, the alendronic acid or salt thereof is contained within the range of 0.1 to less than 70 mg, preferably 0.1 to 40 mg, the absorption increasing agent 1 to 1000 mg is preferably contained in the range of 5 to 500 mg, and an absorption enhancer is contained in the range of 1 to 1000 mg, preferably 10 to 500 mg.

In addition, the present invention may be formulated into an oral dosage form of alendronic acid by adding a conventional pharmaceutically acceptable carrier, adjuvant, excipient, and the like to the composition having the above composition and composition ratio. Oral dosage forms can include, for example, tablets, capsules, troches, solutions, suspensions, granules, powders, and the like, as conventional formulations in the pharmaceutical art. It is more preferable to formulate the preparation of the alendronic acid of the present invention so that it can disintegrate or elute sufficiently in the gastrointestinal tract so as to exhibit maximum absorption in the gastrointestinal tract. In the case of the alendronic acid preparation of the present invention, disintegration under conditions of stomach (37 ° C., pH 1.2 to 4.0 conditions) is eluted within 15 minutes, and elution (paddle method, 50 rpm) is eluted at least 85% in 30 minutes. [Example 3]

In formulating an oral dosage form using the alendronic acid preparation composition of the present invention, the alendronic acid or a salt thereof may be contained within a range of 0.1 to less than 70 mg based on a single unit dose.

The present invention is prepared by adding an absorption increasing agent and an absorption increasing auxiliary agent to the alendronic acid or a salt thereof as an active ingredient, to prepare an alendronic acid formulation containing a smaller amount of the active ingredient, once a week, twice a week, Taking it periodically, on a continuous schedule once every two weeks, once every three weeks, or once every four weeks, is an example of a method of treating osteoporosis. In addition, the invention contains less than 70 mg, preferably less than 40 mg, particularly preferably 37 mg, of alendronic acid or salts thereof, and periodically according to a continuous schedule having a periodicity once a week Taking is shown as an example of a more preferred method of treating osteoporosis.

In addition, the present invention contains 18.5 mg of alendronic acid or a salt thereof as a single dose, and provides one example of a method for preventing osteoporosis by periodically taking a continuous schedule having a periodicity once a week.

As described above, the alendronic acid formulation of the present invention contains an alendronic acid or a salt thereof as an active substance, and the absorption increases the absorption of the active substance in the gastrointestinal tract, particularly the gastrointestinal tract, in vivo. And the composition of the complex containing a complex-forming substance as an absorption enhancer to help increase the absorption of the active substance by the absorption enhancer in the stomach area, and thus has the effect of enhancing the bioavailability of the drug. This has the effect of reducing the single dose as compared to commercially available products generally applied to periodic therapy. Therefore, the present invention is an advanced invention that solves all the disadvantages of the alendronic acid formulations which have been applied to the existing daily continuous therapy and periodic therapy at once.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1.

In the formulation of the alendronic acid formulation according to the present invention, the following experiment was conducted to determine the increase in the absorption rate of the alendronic acid drug according to the type of the absorption enhancer.

37 mg of alendronic acid as an active ingredient and a pharmaceutically acceptable excipient with a composition as shown in Table 1 below were used to prepare tablets in the usual manner [according to the method for preparing tablets of the Korean Pharmacopoeia General Test Method]. Each test group consisted of six healthy persons, and each test group subject was orally administered to each prepared tablet, and the drug excreted through urine for 24 hours was quantified by HPLC-FD. The results are shown in Table 1 below.

The effect of increasing the alandronic acid bioavailability of complexing materials such as sodium EDTA and sodium citrate was insignificant or minimal in clinical trials, unlike prior art in vitro and rat animal studies. In contrast, sodium lauryl sulfate was most effective as an absorption enhancer. Therefore, the use of sodium EDTA and sodium citrate as absorption enhancers was inappropriate.

Example 2.

The following experiment was conducted to investigate the effect of the interaction of the absorption enhancer in the alendronic acid formulation composition.

37 mg of alendronic acid as an active ingredient was contained, and a pharmaceutically acceptable excipient was contained in the composition shown in Table 2 below to prepare a tablet according to a conventional method (according to the method for preparing tablets of the Korean Pharmacopoeia General Test Method). Each test group consisted of six healthy persons, and each test group subject was orally administered to each prepared tablet, and the drug excreted through urine for 24 hours was quantified by HPLC-FD. The results are shown in Table 2 and FIG. 1, respectively.

According to the results of Table 1 and Table 2, the inclusion of the complexing material alone had little or no effect of increasing the bioavailability of the alendronic acid or salts thereof, and only when the absorption increasing agent and the complexing material were contained together. It was confirmed that the effect of increasing the bioavailability was remarkable.

Therefore, the alendronic acid formulation of the present invention cannot achieve the desired bioavailability enhancing effect by the sole inclusion of the complexing material, and only when the complexing material is contained together with the absorption increasing agent as the absorption increasing aid. This makes it possible to achieve the desired increase in bioavailability.

In addition, according to the results of Table 2, it was confirmed that the absorption rate increased when sodium lauryl sulfate, an absorption increasing material, was used at 6% by weight or more of the content of the allandronic acid. In other words, US Patent No. 4,980,171 limited the absorption range by limiting the content range of the absorption increase to 1.5 to 6% by weight, but in the present invention, there is a limit to increase the absorption rate, the present invention contains the absorption increase to the maximum content range pharmaceutically acceptable Since it is possible to further increase the absorption rate of the alendronic acid drug, it is possible to obtain an effect that can reduce the dose of the drug.

Example 3.

In order to determine the dissolution time and disintegration time under gastric conditions for the preparation of the alendronic acid according to the present invention, the following experiment was performed.

Disintegration and dissolution experiments of Example 1 were carried out under the conditions of disintegration test method and dissolution test method paddle method (50 rpm) of the Korean Pharmacopoeia (37 ℃, pH 1.2 to 4.0 conditions) conditions.

Example 4.

In order to determine the degree of absorption of the alendronic acid tablets according to the present invention and a commercially available product (Posmaxmax 70 mg) administered once a week, the following experiment was performed.

Posamax 70 mg contains 91.37 mg of sodium allandronate (70 mg as alendronic acid) as a main ingredient, according to PDR (58th Edition, 2004), and contains as an excipient microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, magnesium stearate The present invention does not include an absorption increaser and an absorption increase aid provided in the present invention.

Next, a tablet was prepared by a conventional method (according to the tablet manufacturing method of the Korean Pharmacopoeia) by containing a composition and a pharmaceutically acceptable excipient as shown in Table 4 below.

Each test group consisted of 8 healthy persons, and each test group subject was orally administered to each prepared tablet, and then the drug excreted through urine for 24 hours was quantified by HPLC-FD. The results are shown in Table 5 below.

According to the results of Table 5, the tablet containing the embodiment 3 according to the present invention (alendronic acid 37 mg) showed a bioavailability equivalent to a commercially available purified product (allendronic acid 70 mg), thereby It can be seen that the preparation of alendronic acid can exhibit an excellent osteoporosis treatment effect even by administering 37 mg once a week. Therefore, the present invention can be expected to reduce the gastrointestinal side effects by reducing the dose compared to conventional commercial products.

 Periodic therapies in which a relatively large amount of drug is administered at regular intervals in order to improve the problems of gastrointestinal damage caused by conventional allendronic acid preparations for the treatment and prevention of osteoporosis, and the disadvantages of gastrointestinal damage noted during such daily doses. The risk of side effects from a single overdose of the drug has been pointed out as a disadvantage.

However, in the present invention, the drawback of the conventionally taken product is to develop an allandronic acid formulation of a novel composition which exhibits an excellent effect of treating and preventing osteoporosis by enhancing the absorption of the alendronic acid drug in the gastrointestinal tract, especially in the stomach. Could be solved at once.

Claims (11)

An active ingredient selected from allenedonic acid and salts thereof; An absorption increasing agent selected from fatty acids, fatty acid derivatives and salts thereof, which exhibits permeability of gastric mucosa and mucus layer; And Selected from EDTA and salts thereof, and citric acid and salts thereof, an absorption increasing aid forming a complex with a divalent or higher metal ion. Alendronic acid oral administration composition for the treatment and prevention of osteoporosis, characterized in that it contains. The method of claim 1, based on a single unit dose Active ingredient less than 0.1 to 70 mg Absorption enhancer 1 to 1000 mg, and 1 to 1000 mg of complexing substance as an absorption enhancer Alendronic acid formulation composition, characterized in that it is contained in the content range. delete The method according to claim 1 or 2, wherein the absorption increasing agent Alendronic acid formulation composition, characterized in that selected from the group consisting of fatty acids or fatty acid derivatives selected from capric acid, sodium caprate, and sodium lauryl sulfate or salts thereof. delete delete The method of claim 1 or 2, wherein the preparation composition is to be taken periodically at a dosage interval selected from the group consisting of once a week, twice a week, twice a week, three weeks, and four weeks. Alendronic acid formulation composition, characterized in that formulated. 8. The formulation of claim 7 wherein the formulation is selected from the group consisting of tablets, capsules, troches, solutions, suspensions, granules and powders. According to claim 8, wherein the formulation composition is disintegration in the gastric conditions (37 ℃, pH 1.2 to 4.0 conditions) within 15 minutes, elution (paddle method, 50 rpm) is more than 85% in 30 minutes Alendronic acid formulation composition, characterized in that. An active ingredient selected from alendronic acid and salts thereof; An absorption increasing agent selected from fatty acids, fatty acid derivatives and salts thereof, which exhibits permeability of gastric mucosa and mucus layer; And An absorption increasing aid selected from EDTA and its salt, and citric acid and its salt, which forms a complex with a divalent or higher metal ion; It contains The active ingredient is a formulation for treating osteoporosis, characterized in that it is formulated to be taken once a week containing 37 mg once a dose based on the content of alendronic acid. An active ingredient selected from alendronic acid and salts thereof; An absorption increasing agent selected from fatty acids, fatty acid derivatives and salts thereof, which exhibits permeability of gastric mucosa and mucus layer; And An absorption increasing aid selected from EDTA and its salt, and citric acid and its salt, which forms a complex with a divalent or higher metal ion; It contains The active ingredient is an allandronic acid preparation for preventing osteoporosis, characterized in that it is formulated to be taken once a week, containing 18.5 mg of a dose based on the content of the alendronic acid.

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