JP2013028603A - Liquid dosage form of proton pump inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid suspension vehicle comprising micro-granules comprising a proton pump inhibitor.SOLUTION: A pharmaceutical composition comprises micro-granules and a liquid suspension vehicle having a pH of less than 6.0 and viscosity sufficient to suspend the micro-granules. The micro-granules having a size of 100-900 μm comprises the proton pump inhibitor (PPI) useful for alleviating the symptoms of commonly gastrointestinal disorders or diseases. The PPI is lansoprazole, which therefore makes the composition, as well as kits for making the composition.

Description

  The present invention relates to liquid dosage forms, and in particular to liquid dosage forms of proton pump inhibitors.

  Many pharmaceutical compounds are susceptible to degradation in an acidic environment. For example, antibiotics (eg, erythromycin), proton pump inhibitors (PPI) (eg, lansoprazole or omeprazole) and pencreatin are compounds that degrade in an acidic environment and are therefore referred to as “acid-labile” . Oral delivery of acid labile pharmaceutical compounds is difficult because the gastric pH is very acidic (usually pH around 1.5-1.9). Under gastric conditions, acid labile drugs usually break down if not protected and are not readily available for ingestion.

  Because of pH sensitivity, acid labile drugs are usually administered in a form that protects the drug from the acidic gastric environment. Enteric coating is probably the most widely used method to protect acid labile drugs from gastric degradation. Enteric coating methods typically form a barrier with a coating that does not dissolve when introduced into the low pH of the gastric environment around the entire dosage form containing drug particles or acid labile drugs. Enteric coatings dissolve at a pH of 6 and above, usually found in the upper small intestine. In this case, the acid labile drug does not degrade sufficiently and is released into an environment where it can be absorbed. Drugs that require enteric coatings are often formulated as capsules or tablets that are difficult to take for patients who have difficulty swallowing, such as pediatric patients, or patients who cannot have swallowing, such as critically ill patients.

  In addition, there are situations that guarantee partial doses of acid labile drugs such as PPI. For example, it is often recommended to take half the normal dose of PPI in patients with liver failure. Although solid dosage forms of PPI are available, these dosage forms are difficult to accurately and reliably subdivide. In particular, there is no means to easily provide the exact portion of the active ingredient contained in a dosage form containing PPI.

  Despite the above, attempts have been made to formulate liquid dosage forms of acid labile drugs. For example, US Pat. No. 5,840,737 recommends dissolving the contents of a commercial capsule containing enteric pellets of PPI in a solution of sodium bicarbonate buffer. In fact, this method requires the doctor to open the capsule and release the enteric PPI into the buffer. Once the capsule contents and buffer are mixed, the mixture is stirred or mixed for about 20-30 minutes so that the enteric coating around the PPI dissolves due to the relatively high pH of the buffer. Once the enteric coating has dissolved, PPI is fairly stable in buffer and can be administered to the patient. However, the volume of buffer used to implement this is quite large, and gas may be generated in the stomach, which may cause stagnation. Snoring is undesirable for patients suffering from gastroesophageal reflux disease (GERD), one of the diseases to which PPI is applied for remission. In addition, the buffer used is usually another component that increases the production cost of the composition. Furthermore, the taste of the solution is unpleasant when administered orally. Because the non-dissolved components of the enteric coating layer tend to form sticky globules that can stick together, sufficient care must be taken to completely dissolve the enteric coating layer from the enteric PPI. Don't be.

  However, none of the currently available liquid dosage forms of PPI can accurately dispense a portion of the active ingredient.

US Pat. No. 5,840,737

  Thus, a liquid dosage form of PPI that maintains the effectiveness of the active ingredient and can be dispensed so that a solid dosage form can be easily administered to patients who have difficulty swallowing and a portion of the active ingredient can be accurately administered from a bulk solution Is desired.

  The present invention provides a liquid dosage form of PPI that is dose titratable and easily administered to patients with difficulty swallowing suffering from gastrointestinal disease. The composition generally comprises microparticles comprising an acid labile drug with an enteric coating; and a liquid suspension vehicle having a pH of less than 6.0 and a viscosity sufficient to suspend the microparticles. . The composition may provide a kit having separate containers that contain the various components of the composition.

  The present invention provides a liquid composition of PPI. A partial dose of the active ingredient can be accurately and reproducibly dispensed from the bulk composition (sometimes referred to as dose titrating). Thus, patients with weak swallowing ability are usually given a partial dose of the active ingredient that is easy to swallow.

  In general, the composition of the present invention uniformly suspends the microparticles of enteric PPI; and a pH that does not dissolve the enteric coating, and a time sufficient to dose titrate a bulk suspension of microparticles. A liquid suspension vehicle having a resulting viscosity. The microparticles usually contain PPI protected with an enteric coating. Any known PPI is suitable for use in the present invention, including but not limited to lansoprazole, omeprazole and pantoprazole. Combinations of PPI and enantiomers and prodrugs of PPI are also suitable for use in the compositions of the present invention. The drug may be formulated with other active or inactive ingredients before applying the enteric coating. For example, a stabilizer such as a Group I metal or Group II metal salt (eg, magnesium oxide, magnesium hydroxide, calcium carbonate or sodium bicarbonate) may be used in the composition to maintain the integrity of the active ingredient. May be. Fillers such as talc, sugars such as sucrose, mannitol and microcrystalline cellulose and other excipients may also be part of the composition.

  Also, a plurality of coatings may be applied to the core formulation before applying the enteric coating layer. Additional coatings are used to protect acid labile drugs where the acid labile drug may react with the enteric coating material. In this case, an additional coating is present between the acid labile drug core and the enteric coating. Commonly used materials for this purpose include, but are not limited to, hydroxypropylcellulose and hydroxypropylmethylcellulose. The use of additional coatings on the microparticles is a choice of those skilled in the art based primarily on the composition of the acid labile drug and the enteric coating material used. Additional coatings are routinely determined experimentally by examining the stability of both enteric microparticles with a subcoating and similar composition microparticles without a subcoating.

  Enteric coatings and methods for applying enteric coatings are known in the art. Enteric coatings generally consist of components that do not dissolve in an environment having a pH of less than 6.0. Normally, the enteric coating of the present invention protects acid labile drugs at the pH of the liquid composition and gastric environment. Any known enteric coating material is suitable for use in the present invention, examples include waxes such as stearic acid, palmitic acid and behenic acid; and cellulose acephthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate Such polymers can be included.

  The microparticles can take a wide variety of forms based on the granulation and sieving method used, but are usually mostly spherical and have a size of 100-900 μm, more preferably 100-700 μm, most preferably 200-500 μm. Have

  Liquid suspension vehicles that can be used in accordance with the present invention have a pH that does not dissolve the enteric coating of particulates. Normally, liquid suspension vehicles having a pH of less than 6.0 do not dissolve the enteric coating. The liquid suspension vehicle may originally have a pH of less than 6.0, or additional components such as acidic excipients may be added to the liquid vehicle to achieve a pH of less than 6.0. An appropriately pH-adjusted buffer is a suitable acidic excipient that can be used for this purpose, and any known buffering agent is suitable for maintaining the pH of the liquid below 6.0. Usually, the pH of the liquid suspension vehicle is less than 6.0, preferably less than 5.5, more preferably less than 5.0.

  Liquid suspension vehicles also serve to maintain the homogeneity of the particulates in the composition. This ability depends mainly on the viscosity of the liquid vehicle. Typically, the liquid suspension vehicle has a viscosity such that the microparticles are homogeneously dispersed in the liquid vehicle for a time sufficient to dispense a uniform dose of the microparticles from the composition after light mixing of the microparticles in the vehicle. So-called “lightly mixed” refers to rotating, shaking or otherwise agitating the contents of the composition for at least 30 seconds, more preferably at least 60 seconds, and even more preferably at least 90 seconds. The resulting fine particle suspension dose can be dispensed immediately after mixing. Thus, the viscosity of the liquid vehicle can maintain the homogeneity of the particulates in the liquid vehicle for at least 15 seconds, preferably at least 30 seconds, more preferably 1 minute, and most preferably 2 minutes. A “homogeneously dispersed” or similar expression used for microparticles in a liquid suspension vehicle is that at least 90% of the desired concentration of the active drug is more preferably at least 95% of the desired concentration of the active drug. It means that it exists throughout. For example, if the concentration of PPI in a particular composition was 100 mg / ml, a 1 ml sample of bulk composition taken at any particular location in the container must contain at least 90 mg of PPI. A composition having a viscosity of 500 cP or more, more preferably 800 cP or more, and still more preferably 900 cP or more is suitable for the above purpose. This viscosity is a value measured using a Brookfield viscometer equipped with a # 3 spindle rotating at 5 rpm.

  The liquid suspension vehicle may inherently have a sufficient viscosity to achieve the above purpose. However, other substances may be added to the liquid to obtain the desired viscosity. Various thickeners for increasing the viscosity of the liquid composition are known. For example, cellulose and its derivatives; gums such as guar gum and xanthan gum; and polymers such as polyvinyl alcohol, polyvinyl pyrrolidone and poloxamers are known excipients that can be used to increase the viscosity of the liquid. The thickening agent can be added to the liquid until the desired viscosity is achieved.

  Due to the nature of the composition of the present invention, the dosage of liquid suspension vehicle can vary greatly. There is no upper limit to the liquid vehicle usage, but practical requirements suggest a volume of usually less than 500 ml, preferably less than 100 ml, more preferably less than 50 ml, most preferably less than 15 ml.

  The concentration of microparticles in the composition can also be varied and is highly dependent on the size of the microparticles and the therapeutically effective amount of PPI in the microparticles. For example, the therapeutically effective amount of PPI can vary from 5 to 300 mg depending on the PPI used. However, in general, a “therapeutically effective amount” means the amount of drug administered to a patient with a frequency that alleviates the gastrointestinal symptoms experienced by the patient being treated. The specific therapeutically effective amount for a specific patient is the disease being treated; the severity of the disease; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; Route of administration; excretion rate of the specific compound used; duration of treatment; drugs used in combination with or together with the specific compound used; and other factors known to those skilled in the medical arts . For example, it is within the skill of one of ordinary skill in the art to begin by administering less doses of the compound than are necessary to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. These factors can then be used to properly administer to a particular patient so that the patient obtains the desired effect.

  The composition can take a variety of configurations. For example, the microparticles are formulated into fast dissolving tablets as described in US Pat. Nos. 5,464,632 and 6,299,904, which are hereby incorporated by reference. Can be done. The tablets may also contain acidic excipients so that the microparticles and acidic excipients are released when the tablets are placed in water. The tablet can also be formulated with a thickening agent. As a result, when the tablet is dissolved in water, for example, the microparticles will be present in a liquid suspension vehicle having an appropriate pH and viscosity. Alternatively, a sachet formulation is also suitable for producing a composition comprising microparticles and a liquid vehicle having a pH of less than 6.0 and sufficient viscosity. Sachets are usually packaged with dry ingredients that may include enteric microparticles of PPI, acidic excipients and thickeners for the purposes of the present invention. Similar to fast-dissolving tablets, a sachet formulation can simply form a composition containing microparticles and a liquid vehicle having a pH of less than 6.0 and a moderate viscosity when placed in water. In a further alternative, the liquid may already have a suitable pH and viscosity, and the addition of microparticles to the liquid results in a formulation. Of course, other components such as flavoring agents, sweeteners, preservatives, colorants and the like may also be added to the composition.

  The composition of the present invention may be provided as a kit comprising a container in which the components of the composition are separately packaged. For example, the kit can include liquid vials and tablets containing the dry ingredients of the composition, such as enteric microparticles, thickeners and acidic excipients. When the tablet is dissolved in a liquid, a completely liquid composition is formed. Of course, the composition may exist as separate components, but these separate components must be mixed prior to administration to form a liquid composition containing microparticles in a liquid vehicle having a pH and viscosity as described above. I must. In the case of a kit, the kit may be accompanied by instructions for proper mixing of the dry and liquid components and an administration device such as a syringe. In the case of a kit, it is preferable that the dry component is completely dispersed in the liquid component within 5 minutes, preferably within 2 minutes, and most preferably within 1 minute.

  Preferably, the composition comprising the PPI of the present invention is for patients suffering from acid reflux disease, gastroesophageal reflux disease, gastric ulcer, duodenal ulcer, or other gastrointestinal diseases to which PPI is applied to ameliorate gastrointestinal disease. To be administered. Thus, there is provided a method for treating gastrointestinal diseases comprising administering the composition of the present invention comprising PPI to a patient in need of treatment such as suffering from gastrointestinal diseases.

  The following examples are presented to further illustrate the invention. These examples do not limit the invention.

[Example 1]
Suspension of microparticles in various liquid suspension vehicles In this example, microparticles containing Lansoprazole® (aPPI) are suspended in various liquid suspension vehicles and a uniform dose is dispensed from the bulk suspension. Investigate what to get.

  In particular, Lansoprazole Fast Dissolving Tables (TAP Pharmaceutical Products Inc., located in Lake Forest, Ill.) Were dissolved in various volumes of water containing different thickeners. Lansoprazole Fast Dissolving Tables (LFDT) consists of enteric microparticles of lansoprazole, mannitol, sweeteners and acidifiers. Due to the acidic excipients in LFDT, the resulting solution has a pH of less than 6.0 upon dissolution. Usually, when LFDT tablets are dissolved in water (30 ml), the pH is less than 5.0. The thickeners used in this experiment were inert ingredients from Smacker's Strawberry Syrup, Citracel (commercially available) and Lansoprazole Sachet (TAP). Lansoprazole sachet inactive ingredient contains about 2.0 g of xanthan gum as a thickener.

  Various suspensions were prepared using LFDT tablets containing the various components described above and lansoprazole (30 mg). The suspension was prepared by putting distilled water and LFDT tablet (1) into a 25 ml capacity bottle and mixing until the tablet disintegrated. It was then added to a 25 ml capacity bottle containing the LFDT tablet with the thickener suspended therein and mixed vigorously. A sample of the suspension was then taken and subjected to HPLC analysis to determine the lansoprazole concentration in the sample. This data was compared to the concentration that must theoretically be present in the sample to reach the “% of theory” shown in the table below (ie, 30 mg / suspension volume). Samples are analyzed at least twice, often three times, and an average value of% of the theoretical measurement is reported. The relative standard deviation (RSD) for the reported% of the theoretical value is also reported. The actual amounts of components tested according to the above procedure and the average% of the theoretical values are shown in Table 2 below.

  As shown in the data in Table 2, the concentration of lansoprazole in a given sample from the suspension was greater than 90% of the theoretical amount of lansoprazole that must be present in the sample.

[Example 2]
Reproducibility of drug amount in suspension In this example, a suspension was prepared in the same manner as in Example 1, and a single sample of each suspension was analyzed. Each sample was prepared using distilled water (10 ml), LFDT tablet (1 piece) and sachet inert ingredient (2 g). The percent of theory for each of the 10 suspensions is shown in Table 3 below. Two additional samples were also taken from sample 10 to see if the% of theory for multiple aliquots from one suspension was reproducible. These results are shown in Table 4 below.

  The theoretical average% for the 10 suspensions described above was 104.5 (RSD 1.90). Suspension No. The average percentage of theory for multiple samples from 10 was 101.3 (RSD 2.8). Samples from multiple different suspensions always yielded a similar theoretical%, and the theoretical% of multiple samples from a single suspension was also constant.

[Example 3]
Acid Resistance of Fine Particles in Liquid Suspension Vehicle In this example, the stability of the active ingredient in the composition was evaluated. Specifically, the stability of the acid labile drug lansoprazole in the composition was examined.

  After dispersing the LFDT tablet (1 piece) in distilled water (10 ml), the sachet inactive ingredient (2 g) was added to the dispersed LFDT tablet. The suspension was mixed for 1 minute. The suspension was poured into a dissolution vessel containing 0.1 N HCl (500 ml) pre-warmed to 37 ± 0.5 ° C. Prior to placing the LFDT suspension into the acid solution, 0.1 N HCl (10 ml) was withdrawn and used to rinse the container containing the LFDT suspension twice (5 ml per rinse). Once the rinse solution was added, the sputum in the dissolution vessel was set to 75 rpm and mixed for 60 minutes. After mixing, a 10 ml aliquot was taken from the dissolution vessel and filtered using a 0.45 um filter. The absorbance of the filtrate at 306 nm (at this wavelength, the by-product of lansoprazole degradation shows absorbance) was spectrophotometrically tested and compared to the absorbance spectrum of LFDT dissolved in distilled water. Table 5 shows the lansoprazole content for four samples of a composition containing a sachet inert ingredient, two samples of LFDT tablets suspended only in water and distilled water treated similarly to the LFDT tablets in the sachet inert ingredient. Percent free.

  As shown in Table 5, the sachet inactive component did not significantly affect the release of lansoprazole from the enteric microparticles.

[Example 4]
Viscosity of Composition In this example, different amounts of thickener (sachet inert component) were added to distilled water and the viscosity of the resulting solution was measured. Viscosity was measured using a Brookfield viscometer equipped with a standard # 3 spindle and temperature probe. Each sample (150 ml) was placed in a 200 ml tall beaker and the viscosity was measured using a spindle rotating at 5 ppm.

  The ratio of the components in each sample (150 ml) (grams of sachet inactive component with respect to 1 ml of water), measurement time, temperature,% scale and measured viscosity are shown in Table 6 below.

  Analysis of the results of Example 1 and the above viscosity results showed that a viscosity of 959 or higher (using the above viscometer parameters) was sufficient to obtain a dose titratable composition. Specifically, a sample taken from the composition prepared in Example 1 using a sachet inert ingredient (0.5 g) in water (10 ml) contained 90% or more of the theoretical concentration of lansoprazole. Moreover, it can be seen from the viscosity results shown in Table 6 that the composition prepared using a large amount (that is, 0.75 g: 10 ml) of the thickener had a viscosity of 959. Thus, if the viscosity is 900 or higher, the microparticles can be kept in suspension for a time sufficient to dispense a suspension dose having at least 90% of the expected active ingredient. Inferring from the above, it is suggested that the viscosity (using the viscometer parameters described above) must be greater than or equal to 500 to suspend the microparticles sufficiently to dose titrate the bulk solution.

  Although the present invention has been described in detail with reference to particular embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments without departing from the spirit and scope of the invention. .

Claims (9)

A composition comprising (a) microparticles comprising a proton pump inhibitor coated with an enteric coating and (b) a liquid suspension vehicle having a pH of less than 6.0 and a viscosity sufficient to suspend the microparticles.   The composition according to claim 1, wherein the fine particles have a size of 100 to 900 µm.   The composition according to claim 1, wherein the composition has a viscosity of 500 cP or more.   4. A composition according to claim 3 wherein the active ingredient is lansoprazole.   A gastrointestinal disorder patient comprising administering to the patient a composition comprising microparticles of an enteric proton pump inhibitor and a liquid suspension vehicle having a pH of less than 6.0 and a viscosity sufficient to suspend the microparticles. Method of treatment.   a) a first container containing a microparticle containing a proton pump inhibitor coated with an enteric coating; and b) a second container containing a liquid, wherein the first or second container further comprises an acidic excipient, A kit in which the first or second container further contains a thickener so that the liquid produced by mixing the contents of the first and second containers has a viscosity sufficient to suspend the microparticles.   The kit according to claim 6, wherein the proton pump inhibitor is lansoprazole.   The kit according to claim 7, wherein the liquid has a viscosity of 500 cP or more.   The kit according to claim 6, wherein the fine particles have a size of 100 to 900 µm.