KR101723266B1 - Immediate release oral composition comprising non-steroidal anti-inflammatory drug and proton pump inhibitor, and method for preparing the same - Google Patents

Abstract

The present invention relates to an inner capsule comprising a non-steroidal anti-inflammatory drug (NSAID) and a proton pump inhibitor (PPI); And an outer capsule comprising an alkaline buffer and surrounding the inner capsule, wherein the composition of the present invention is configured in the form of a double capsule encapsulating the outer part with an alkaline buffer so that the pH of the gastric environment To increase the solubility of the pH-dependent drug, and to improve the solubility and dissolution of the drug by converting the crystalline form of the drug into an amorphous form, so that the drug can be effectively used as a rapid-acting composition without being affected by pH.

Description

[0001] The present invention relates to a non-steroidal anti-inflammatory drug and a proton pump inhibitor, and a method for preparing the same.

The present invention relates to an oral accelerating composition comprising a nonsteroidal antiinflammatory drug and a proton pump inhibitor and a process for their preparation.

Nonsteroidal anti-inflammatory analgesic drugs (NSAIDs) are drugs mostly used in the treatment of mild to moderate pain including osteoarthritis and headache, migraine, menstrual cramps and muscle aches, but have various side effects. Side effects that occur in 20% to 40% of NSAID users occur mostly in the stomach and small intestine, and typically represent symptoms such as indigestion (stomach, heartburn, hypertension or nausea), erosion, gastritis / duodenitis and ulcer, Anemia due to hemorrhage can be induced, and in severe cases even a life threatening can be achieved (see Non-Patent Document 1). The best alternative to avoiding these side effects is to take acidic inhibitors such as proton pump inhibitors (PPIs).

On the other hand, a representative example of a composite composition of an NSAID and a proton pump inhibitor is a commercially available product, Vimovo. Non-mosquito is a formulation in which magnesium tablets coated with intestinal tablets of naproxen are coated with magnesium (see Patent Document 1). However, there is a disadvantage in that it is difficult to coat the exact amount of drug during mass scale production, and it must be dissolved in at least one solvent in order to coat magnesium, which is poor in liquid stability.

1. U.S. Patent No. 6,926,907

1. Henryda et al., Br Med J (Clin Res Ed). 1987 Nov 14, 295 (6608): 1227-9

Accordingly, it is an object of the present invention to provide an oral accelerating composition having increased water solubility and dissolution rate of NSAID and PPI in gastric environment.

It is another object of the present invention to provide a process for preparing the oral composition.

In order to achieve the above object, the present invention provides an inner capsule comprising a non-steroidal anti-inflammatory drug (NSAID) and a proton pump inhibitor (PPI); And an outer capsule surrounding the inner capsule and comprising an alkaline buffer.

The present invention also relates to a method for preparing an inner capsule comprising a non-steroidal anti-inflammatory drug (NSAID) and a proton pump inhibitor (PPI); Preparing an external capsule comprising an alkaline buffer; And enclosing the inner capsule on the outer capsule. The present invention also provides a method for preparing an oral composition for oral use.

The oral composition for oral administration according to the present invention is constituted in the form of a double capsule encapsulating the external surroundings with an alkaline buffer to increase the solubility of the pH-dependent drug by controlling the pH of the stomach environment and to convert the crystalline form of the drug into amorphous form, And thus can be usefully used as a rapid-release composition which is not affected by pH.

Figure 1 is a schematic representation of the composition and action of the oral composition for oral administration according to the present invention.
Fig. 2 is a graph showing the water solubility of a solid dispersion containing fl oviprofen and esmeprazole according to the change of the hydrophilic polymer content.
In Figure 3, A is an image of a floriprofen powder, B is an image of an Esmeprazole powder, C is an image of polyvinylidone (PVPK-30), D is an image of (flurbiprofen, PVPK-30), and E is the image of the solid dispersion (F8) of Table 1 in Example 1.
Figure 4 shows the temperature recording results through thermal analysis, where A is a flrobiprofen powder, B is an esmeprazole powder, C is PVPK-30, D is fluobiprofen, esmeprazole and PVPK- 30), and E is the solid dispersion (F8) of Table 1 in Example 1.
5 is a graph of morphological change measured by powder X-ray diffraction (P-XRD), wherein A is a floriprofen powder, B is an emmeprazole powder, C is a PVPK-30 , D is a physical mixture of (flurbiprofen, esmeprazole and PVPK-30), and E is the solid dispersion (F8) of Table 1 in Example 1.
6 is a graph showing the acid neutralization capacity of the water-soluble or water-insoluble alkalizing agent, and B is a graph showing the optimization ratio of the water-soluble or water-insoluble alkalizing agent mixture.
Fig. 7 is a graph showing elution of a mixture of a flrobiprofen / esmeprazole powder and a floibifrophen / esmeprazole-containing solid dispersion under conditions of artificial gastric juice and purified water.

The oral composition for oral administration of the present invention will be described in more detail below.

The present inventors prepared an inner capsule containing a solid dispersion composite of PPI such as NSAIDs and Esmeprazole such as floripifopen using a spray drying technique in which the drug is converted from a crystalline form to an amorphous form and increased in solubility, The present invention was completed by constructing an oral composition which is surrounded by an external capsule containing a buffer to improve the water solubility with simultaneous immediate release of the composition.

The inner capsule of the oral composition for oral administration according to the present invention may contain a non-steroidal anti-inflammatory drug (NSAID).

Wherein the NSAID is selected from the group consisting of flurbiprofen, acetylsalicylic acid, indomethacin, diclofenac, piroxycam, tenoxycam, ibuprofen, naproxen, ketoprofen, nabumetone, ketorolac, azapropazone, mefenamic acid, Pharmacologically acceptable salts thereof, such as, for example, sulindac, diflunisal, thiaprofen, acethethacin, aceclofenac, droxycam, oxaprozin, flotaphenin, phenylbutazone, proglumethacin, tolmetin, A salt thereof, a salt thereof, a precursor thereof, and a mixture thereof, and preferably a flowbipropene can be used, but is not limited thereto.

The inner capsule of the oral composition for oral administration according to the present invention may contain the NSAID in an amount of 10 mg to 300 mg, preferably 30 mg to 100 mg, per unit dosage form, but is not limited thereto. If the content of NSAID is out of the above range, it may cause gastrointestinal disorder caused by NSAID and lower efficacy below expected value.

The inner capsule of the oral composition for oral administration according to the present invention may contain a proton pump inhibitor (PPI).

The PPI may be selected from the group consisting of esmeprazole, dexlanthoxazol, lansoprazole, omeprazole, pantoprazole, rabeprazole, tenatoprazole, pharmaceutically acceptable salts thereof, precursors thereof and mixtures thereof And preferably Esmeprazole may be used, but is not limited thereto.

The inner capsule of the instant oral composition according to the present invention may contain, but is not limited to, the PPI in an amount of 1 mg to 100 mg, preferably 5 mg to 20 mg, per unit dosage form. If the content of PPI is out of the above range, the gastrointestinal irritation caused by the NSAID may not be suppressed or may cause a problem affecting digestion.

In the present invention, a solution selected from the group consisting of ethanol, water, methanol and a mixture thereof may be used for the dissolution of the NSAID and PPI, and ethanol is preferable but not limited thereto.

In particular, as a NASID, flurbiprofen is a potent non-steroidal anti-inflammatory analgesic used in the treatment of arthritis pain and inflammation. It exhibits a strong anti-inflammatory effect when administered orally, but has side effects such as gastrointestinal irritation and other systemic side effects Esmeprazole as a PPI inhibits gastric acid secretion. It is rapidly degraded at a low pH and is sensitive to light and heat. Therefore, As a result of the necessity of a complex formulation of sol, it is possible to produce an inner capsule using esperprazole as a PPI and fluvifrophen as a NASID as an embodiment of the present invention.

 The inner capsule of the oral composition for oral administration according to the present invention may further contain a hydrophilic polymer and an alkalizing agent.

The hydrophilic polymer serves to increase the water solubility of the drug in the present invention. Examples of the hydrophilic polymer include polyvinylpyrrolidone (PVPK-30), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) Methylcellulose sodium, and polyvinylpyrrolidone (PVP K-30) may be preferably used. However, the present invention is not limited thereto.

The inner capsule of the oral composition for oral administration according to the present invention may contain the hydrophilic polymer in an amount of 10 mg to 500 mg, preferably 50 mg to 200 mg, per unit dosage form, but is not limited thereto. At this time, when the content of the hydrophilic polymer is out of the above range, the water solubility may decrease.

The alkalizing agent may be selected from the group consisting of sodium carbonate, potassium hydrogencarbonate and calcium carbonate by controlling pH during dissolution in the present invention, and preferably sodium carbonate may be used. However, the present invention is not limited thereto.

In the present invention, the dissolution of the hydrophilic polymer may be performed using a solution selected from the group consisting of water, ethanol, methanol, and a mixture thereof, but is not limited thereto.

The inner capsule of the oral composition for oral administration according to the present invention may contain the alkalizing agent in an amount of 5 mg to 100 mg, preferably 10 mg to 50 mg, per unit dosage form, but is not limited thereto. At this time, if the content of the alkalizing agent is out of the above range, the drug may be decomposed or precipitated.

In the present invention, a solution selected from the group consisting of water, glycerol, and a mixture thereof may be used for dissolving the alkalizing agent, but water is preferable, but not limited thereto.

The inner capsule of the oral composition for oral administration according to the present invention is prepared by dissolving NSAID and PPI in ethanol to prepare a drug mixture; Dissolving the hydrophilic polymer and the alkalizing agent in water to prepare a stabilizer; Mixing the drug mixture with a stabilizer; Spray-drying the mixed mixture; Pulverizing the spray dried mixture; And encapsulating the powdered mixture.

In the spray drying, the spraying pressure is 1 to 6 kg / cm < ² > , And the drying air is refined by setting the intake system to 10 at a pressure of -25 mbar in the suction pipe, but is not limited thereto. At this time, if the condition is exceeded, a problem that spraying can not be performed uniformly may be caused.

The external capsule of the oral composition for oral administration according to the present invention may contain a water-soluble alkalizing agent, a water-insoluble alkalinizing agent or a mixture thereof.

The water-soluble alkalizing agent may be selected from the group consisting of sodium hydrogencarbonate, disodium hydrogen phosphate, and sodium tertiary phosphate, and serves to adjust the pH during the dissolution of the composition in the present invention. May be selected from the group consisting of magnesium hydroxide, calcium carbonate and magnesium oxide. Preferably, the water-soluble alkalizing agent can be sodium hydrogen carbonate The water-insoluble alkalizing agent may be magnesium hydroxide, but is not limited thereto.

The water-soluble alkalizing agent and the water-insoluble alkalizing agent can be mixed at a weight ratio of 2: 1, and preferably at a weight ratio of 1: 1, but are not limited thereto.

The external capsule of the oral composition for oral administration according to the present invention may contain a mixture of the water-soluble alkalizing agent and the water-insoluble alkalizing agent in an amount of 100 mg to 500 mg, preferably 200 mg to 250 mg per unit dosage form, But is not limited thereto. If the content of the alkalizing agent deviates from the above range, the pH of the solution may not be controlled at the time of dissolution, and stability of the drug may be lowered, thereby causing problems such as decomposition.

The oral composition for oral administration of the present invention is prepared by enclosing the inner capsule on an outer capsule according to an encapsulation method well known to those skilled in the art.

The oral compositions comprising the inner capsules and the outer capsules are insoluble at pH 6 to 8 and are soluble at pH 0 to 3, so they can be usefully used for drugs that operate above pH 1.2.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

< Example  1> Dissolution of solid dispersant according to the content of alkalizing agent

In order to investigate the dissolution of the solid dispersant according to the change of the added alkalizing agent content, a flobifrophen / esemeprazole-containing solid dispersion was prepared using a mini-spray dryer (Flawil, Switzerlane). One solution was prepared by dissolving 1 g of flobifroprene sieved in water and 0.1 g of esmephalazole in 100 mL of ethanol, and then 0.5 g of PVPK-30 and sodium carbonate were dissolved in 100 mL of water to prepare two solutions. Then, one solution and two solutions were mixed. At this time, as shown in Table 1, the amount of sodium carbonate was changed until a clear homogeneous transparent solution was obtained.

As shown in F1 to F3 in Table 1, when sodium carbonate was not added or a small amount of 0.1 or 0.2 g was added, results indicating the decomposition of the emmeprazole in which the color of the solution changed from dark pink to light yellow could be confirmed. On the other hand, when 0.5 g of a large amount of sodium carbonate was added as in F5, precipitation of the drug was observed.

When 0.3 g or 0.4 g of sodium carbonate was added as in F4 to F5, a transparent uniform solution was obtained, and based on this, the composition according to the composition of F4 and F5 was spray dried. The spraying pressure was 4 kg / cm ² , And the fine granulation of dry air was maintained by setting the intake system to 10, the pressure of the suction pipe was -25 mbar.

< Example  2> Evaluation of water solubility of composition according to change of hydrophilic polymer content

To investigate the solubility of the solid dispersant according to the content of the added hydrophilic polymer, an excess of the solid dispersion prepared by various amounts of the transporter was added to 1 mL of water. Then, all the samples were mixed evenly at 100 rpm for 5 days in a 25 ° C isothermal water bath, centrifuged at 10,000 × g for 10 minutes, and the supernatant was passed through a 0.45 μm membrane filter. The filtered samples were diluted to the mobile phase via HPLC method to obtain the appropriate concentration for the determination of flurbiprofen and esmefrozole.

To find the optimal amount of hydrophilic polymer, a solution of F4, F7 and F8 in Table 1 consisting of 0.5 g, 1 g and 1.5 g of PVPK-30 was prepared and spray-dried.

As shown in FIG. 2, when both the flobiforpen and the esmeprazole powder were compared with each other, the solubility of the two drugs increased as the amount of the hydrophilic polymer increased in the solid dispersion. In particular, the solubility of the solid dispersion of F8 was increased to 3600 times for fluvifrophen and 15 times for emmeprazole, respectively, as compared with the drug powder.

< Example  3> Morphological analysis

S-4100 scanning electron microscope (SEM, Hitachi, Tokyo, Japan) was used for morphological analysis. Physical blends of flurbiprofen powder, esmeprazole powder, PVPK-30, (flurbiprofen, esmeprazole and PVPK-30) and the form of the solid dispersion (F8) of Table 1 were compared with each other. The samples were fixed to a brass slice using double-sided tape and coated with platinum (6 nm / min) at 150 mA for 120 seconds in a vacuum (6 Pa) with an ion evaporator (Hitachi Ion Sputter (E-1030) made. SEM images were analyzed using an image analysis system (ImageInside Ver 2.32).

As shown in A to B in Fig. 3, in the case of the fl oviprofen powder and the esmeprazole powder, a smooth surface and an irregular crystalline particle shape were shown. On the other hand, in the case of PVPK-30 like C, amorphous spherical particles were observed. Also, like D, the physical mixture of (flurbiprofen, esmeprazole and PVPK-30) is such that irregular crystalline particles of some flurbiprofen powder and esmeprazole powder are attached to PVPK-30 Respectively. Alternatively, as in E, the spray-dried solid dispersion (F8) of Table 1 showed spherical amorphous particles with smooth surface.

< Example  4> Heat flow analysis

To analyze the change in morphology, physical mixtures of flurbiprofen powder, esmeprazole powder, PVPK-30, (flurbiprofen, esmeprazole and PVPK-30) and the solid dispersion of Table 1 F8) was measured by differential scanning calorimetry (DSC Q200 v24.2 build 107, TA Instruments, New Castle, DE, USA).

1.5 mg samples were placed in an aluminum pan and dry nitrogen was used as the effluent gas. All samples were scanned at 40 ° C to 350 ° C at a ramp rate of 10 ° C / min.

As in FIG. 4A, the fl oviprofen powder showed one sharp endothermic peak consistent with the characteristic melting point and crystalline nature at 115 ° C. As with B, the esmeprazole powder showed an exothermic peak at 180 ° C. On the other hand, like C, PVPK-30 did not have a distinct peak but showed a small and broad endothermic peak in the range of 50-110 ° C. D, the physical mixture of (flurbiprofen, esmeprazole and PVPK-30) exhibited both an endothermic peak and an exothermic peak of flurbiprofen and esmeprazole, but a weak interaction between drug and transporter There was a decrease in strength due to. On the other hand, as with E, the solid dispersion (F8) of Table 1 showed similar peaks as PVPK-30.

< Example  5> Morphological Change Analysis Powder  X- ray diffraction , P- XRD )

 Physical blends of flurbiprofen powder, esmeprazole powder, PVPK-30, (flurbiprofen, esmeprazole and PVPK-30) and the P-XRD pattern of the solid dispersion (F8) Ray diffractometer (X'Pert PRO diffractometer, PAN analytical, Netherlands). (Γ = 1.5406 Å) at 30 mA and 40 kV from 10 ° to 60 ° in the 2θ range at an angular rate of increase of 0.02 ° / s at room temperature.

As in Figs. 6A to 6B, the diffraction pattern of fl oviprofen, esmeprazole exhibited a number of intrinsic peaks at various angles consistent with the crystalline nature of the material up to 40 °. On the other hand, like C, PVPK-30 did not have a clear inherent peak due to the amorphous nature of the polymer. D, the crystal form was still present in the diffraction curves of the physical mixtures of (flurbiprofen, esmeprazole and PVPK-30) due to the low intensity of the peaks of fluvifrophen and esmeprazole . However, as with E, the solid dispersion (F8) of Table 1 showed similar peaks as PVPK-30, indicating a perfect interaction between flubifrophen, esmeprazole, PVPK-30, Dispersed, from hydrophobic (crystalline) to hydrophilic (amorphous) forms in the solid dispersion.

Therefore, the results of SEM, DSC and P-XRD have demonstrated that the dispersion of drug into the receptor and the conversion of hydrophobic (crystalline form) to hydrophilic (amorphous form) increased the aqueous solubility of the fluvifrophen and the esmeprazole .

< Example  6> To the alkaline agent  Following pH  Change analysis

To investigate the acid neutralization capacity of the water-soluble or water-insoluble alkalizing agent, various alkalizing agents or mixtures thereof were dissolved in 250 ml of artificial gastric juice (40 mL of 0.1 N HCl + 210 mL of purified water; pH 1.70) and the pH change was measured.

As shown in FIG. 6A, sodium bicarbonate and magnesium hydroxide showed the highest pH rise. Also, as in B, when mixed at a ratio of 1: 1, the initial pH increase was further increased, which was in agreement with the sum of the effects of buffers. The mixing of sodium hydrogencarbonate and magnesium hydroxide increased the pH to 7.6 at a total amount of 250 mg. Increasing the total amount from 250 mg to 300 mg results in a very small increase in pH due to saturation of the acidic neutralizing capacity of the buffers. For this reason, the optimal amount of alkaline buffer was determined to be 250 mg consisting of sodium hydrogencarbonate and magnesium hydroxide in a 1: 1 ratio.

< Example  7> Elution analysis

In order to analyze the elution degree of the oral composition prepared in Example 1, the solid dispersion (F8) of Table 1 containing the mixture of the fl oviprofen / esmeprazole powder and the fl oviprofen / ) Were used for the dissolution experiment in artificial gastric juice and purified water. In the same manner, 50 mg of fluobiprofen and 5 mg of esmeprazole were added to a No. 1 capsule, and the mixture was placed in No. 0 capsule containing an alkalizing agent (sodium hydrogencarbonate: magnesium hydroxide = 1: 1). The elution test was carried out at 36.5 ° C using the first method (rotating specimen method) at a rotation speed of 50 rpm in purified water and artificial gastric juice.

As a result, as shown in FIG. 7, in both the artificial gastric juice and water conditions, the solid dispersions were found to release 80% or more of flurbiprofen and esmeprazole in 30 minutes, which was significantly higher than that of the drug powder (p < 0.05). The solvent was initially exposed to the buffer through the disintegration of the outer capsule for 2-3 minutes and the subsequent neutralization of the solvent through the disintegration of the inner capsule resulted in an increase in the pH of the eluting solvent and no decomposition of the esmeprazole. Thus, it was confirmed that the oral composition for oral administration according to the present invention inhibits the degradation of the emmeprazole by making the base environment of the solvent.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. It is to be understood that various modifications and changes may be made without departing from the scope of the appended claims.

Claims (10)

A non-steroidal anti-inflammatory drug (NSAID), a proton pump inhibitor (PPI) and polyvinylpyrrolidone in a weight ratio of 1: 0.1: 1.5, and spherical amorphous particles An inner capsule comprising a solid dispersion having a shape; And
And an external capsule containing an alkaline buffer surrounding the internal capsule and containing sodium bicarbonate and magnesium hydroxide in a weight ratio of 1: 1. The method according to claim 1,
Wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of fluobifopen, acetylsalicylic acid, indomethacin, diclofenac, piroxycam, tenoxicam, ibuprofen, naproxen, ketoprofen, nabumetone, ketorolac, azapropazone, Aceclofenac, droxycam, oxaprozin, flotaphenone, phenylbutazone, proglumethacin, tolmetin, penbufen, and the like. &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, a precursor thereof, and mixtures thereof. The method according to claim 1,
Wherein said proton pump inhibitor is selected from the group consisting of Esomeprazole, Dexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Tenatoprazole, A pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a precursor thereof, and a mixture thereof. The method according to claim 1,
Wherein the nonsteroidal antiinflammatory drug is flowibrophen and the proton pump inhibitor is an esmeprazole. The method according to claim 1,
Wherein the inner capsule further comprises an alkalizing agent selected from the group consisting of sodium carbonate, potassium bicarbonate, and calcium carbonate. delete delete 6. The method according to any one of claims 1 to 5,
Wherein said oral composition is insoluble at a pH of from 6 to 8 and dissolved at a pH of from 0 to 3. A non-steroidal anti-inflammatory drug (NSAID), a proton pump inhibitor (PPI) and polyvinylpyrrolidone in a weight ratio of 1: 0.1: 1.5, and spherical amorphous particles Preparing an inner capsule comprising a solid dispersion having a shape;
Preparing an external capsule comprising an alkaline buffer containing sodium hydrogencarbonate and magnesium hydroxide in a weight ratio of 1: 1; And
And encapsulating the inner capsule on the outer capsule. &Lt; Desc / Clms Page number 19 &gt;


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