JP2007302688A - Quick-acting formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an enteric-coated quick-acting formulation of pyridoxine hydrochloride and doxylamine succinate. <P>SOLUTION: The quick-acting formulation is characterized in that when it is measured with a type 2 elusion testing device at 37°C in a phosphate buffer, (a) at least about 40% of the entire weight of pyridoxin hydrochloride and doxylamine succinate is eluted after 30 min from the start of the test, (b) at least about 70% of the entire weight is eluted after 60 min, (c) about 80% of the entire weight is eluted after 90 min, and (d) at least about 90% of the entire weight is eluted after 120 min after the start of the test. A desirable example of the formulation has a core having at least one layer of an enteric-soluble coating, wherein the core comprises pyridoxine hydrochloride, doxylamine succinate, an extender or a binder as an inert excipient, a disintegrator, a lubricant, a silica flow conditioner, and a stabilizer. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a fast-acting formulation, preferably a tablet having an enteric coating, which is a drug containing a pair of active ingredients having a synergistic action, doxylamine succinate and pyridoxine hydrochloride (hereinafter abbreviated as “DS-P”). Is a fast-acting formulation. DS-P is useful for the treatment of nausea and vomiting, and is particularly useful for pregnancy nausea and vomiting (hereinafter abbreviated as “NVS”), but is not limited thereto. The present invention therefore relates to all therapies for which application of DS-P is known and to treatments implemented in the future.

  DS-P pharmaceutical formulations are known. A formulation called Diclectin (manufactured by Duchesnay Inc.) currently marketed in Canada contains pyridoxine hydrochloride and doxylamine succinate as active ingredients. In addition, dictin contains lactose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide and magnesium stearate as excipients.

  Declectin is the world's most studied pharmaceutical for safety during pregnancy. Due to its excellent safety properties, dictin is the most suitable pharmaceutical for the treatment of NVP. Current formulations are coated with sucrose and have several drawbacks. One of them is delayed action. In the current formulation, it takes 4 hours or more after ingestion to almost completely elute the two active ingredients (pyridoxine hydrochloride and doxylamine succinate) in the small intestine where the active ingredients are absorbed. This time is often considered too long for patients who want to relieve symptoms urgently, such as women suffering from NVP.

  Another drawback of current prescriptions relates to patient compliance. Women suffering from NVP frequently complain of olfactory hypersensitivity, which means that various odors and tastes can cause nausea and vomiting. In addition to the use of organic solvents and phthalates in the current production of enteric coatings, the odor and taste of sucrose coated with the current formulation can also prevent pregnant women from taking this drug. I'm worried.

  There is also a problem with the size of tablets currently on the market. Because women suffering from NVP often have problems with swallowing, small tablets improve patient compliance. In addition, small tablets may appear more harmless than large tablets, and the patient may have the impression that they are taking a small amount of medication. As a result, patient compliance will be significantly increased.

  Finally, the current formulation contains lactose. Therefore, patients suffering from lactose intolerance cannot be taken.

  Accordingly, it would be desirable to provide improved fast-acting formulations that overcome the shortcomings of the prior art to patients suffering from nausea and vomiting.

  However, since DS-P is taken orally as a tablet with an enteric coating, the new oral formulation must pass intact through the stomach and when the tablet reaches the intended arrival point, i.e. the intestine. The two active ingredients must be released immediately.

  The main problem that has to be solved by the present invention is to provide a dosage form that administers a pair of active ingredients exhibiting synergism as a fast acting formulation and overcomes the disadvantages of the prior art. It was important to provide a formulation in which the two active ingredients show similar elution curves so that the elution of one active ingredient does not interfere with the elution of the other active ingredient. This was also important from the viewpoint of the synergistic therapeutic effect of the two active ingredients.

SUMMARY OF THE INVENTION In summary, the present invention is a novel aqueous enteric coated formulation including DS-P, and its dissolution characteristics indicate that it is a fast acting formulation.

  Furthermore, the present invention provides pharmaceutical compositions having specific in vitro dissolution characteristics that demonstrate the rapid efficacy of the active ingredient. This pharmaceutical composition is suitable for simple and repeated manufacture.

  Further applicability of the present invention will become apparent from the detailed description below. However, since the spirit and scope of the invention and various modifications and improvements within its scope will be apparent to those skilled in the art, this detailed description merely exemplifies preferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION Other objects and features of the present invention can be understood from the following detailed description to illustrate preferred embodiments of the invention.

  In a broad sense, the present invention provides a fast-acting formulation containing pyridoxine hydrochloride and doxylamine succinate.

  The formulations of the present invention can be used in the medical and veterinary fields when nausea and / or vomiting symptoms require drug intervention. Since the formulation of the present invention is intended for therapeutic purposes, the formulation and its components must be pharmaceutically acceptable. Preferred formulations are oral dosage forms such as tablets, pills or beads packed in capsules or solutions. The most preferred formulation is a tablet. It is preferable that the tablet of the present invention can pass through the stomach intact. To test for this feature, the tablets of the present invention were tested to resist disintegration for at least 1 hour in the surrogate gastric fluid “SGF”.

According to the present invention, the formulation is preferably a high-speed liquid in elution characteristics under conditions of 100 rpm per minute using a type 2 dissolution test apparatus at 37 ° C. in 1000 ml of a phosphate buffer solution of pH 6.8. When measured by chromatography, the following elution characteristics are satisfied.
(A) at 30 minutes after the start of the test, at least about 40% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes;
(B) at least about 70% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate at 60 minutes after the start of the test;
(C) 90 minutes after the start of the test, at least about 80% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes;
(D) At the time of 120 minutes after the start of the test, at least about 90% of the total amount of pyridoxine hydrochloride and doxylamine succinate elutes.

  In the present invention, any statement regarding elution characteristics is based on the amount of released pyridoxine hydrochloride and doxylamine succinate listed in United States Pharmacopoeia at 37 ° C. in 1000 ml of pH 6.8 phosphate buffer. This is based on the result of the dissolution test measured by high performance liquid chromatography under the condition of 100 rpm per minute using the type 2 dissolution test apparatus.

  As used herein and in the claims, an “enteric coating” is a coating consisting of one or more layers that is resistant to disintegration in human gastric fluid, but not only a coating that disintegrates in human intestinal fluid, Furthermore, it means a coating that disintegrates very slowly in human gastric fluid but rapidly disintegrates in human intestinal fluid. In a broad sense, an “enteric coating” is applied to the tablet's compressed core prior to the true enteric coating, as well as any finished cosmetic coating applied over, for example, the true enteric coating. Includes any seal coating.

  In the most preferred embodiment, the formulations of the present invention contain a core coated with an aqueous enteric coating. This core includes the active ingredients pyridoxine hydrochloride and doxylamine succinate, as well as the inactive ingredients filler or binder, disintegrant, lubricant, silica flow conditioner and stabilizer. To do.

  Examples of extenders or binders include gum arabic, alginic acid, calcium hydrogen phosphate (dibasic), carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, dextrates ), Sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethyl cellulose, disodium hydrogen phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, Glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate (magnes ium aluminum silicate), maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch and zein. The most preferred bulking agent or binder is microcrystalline cellulose.

  Examples of disintegrants include alginic acid, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose (low substitution), microcrystalline cellulose, cellulose powder, colloidal silicon dioxide, sodium croscarmellose, crospovidone ( crospovidone), methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, disodium pyrosulfite, disodium edathamil, sodium edetate, ethylenediamine Disodium tetraacetate (EDTA), cross-linked polyvinyl pyrrolidines, pregelatinized starch, carboxymethyl starch, carboxy Sodium carboxymethyl starch and microcrystalline cellulose are included. The most preferred disintegrant is sodium crosscarmelose.

  Examples of lubricants include calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil (type I), magnesium oxide, magnesium stearate, mineral oil, poloxamer ( poloxamer), polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc, zinc stearate, glyceryl behenate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, benzoic acid Sodium / sodium acetate (mixture) and DL leucine are included. The most preferred lubricant is magnesium stearate.

  Examples of silica flow conditioners include silicon dioxide and aluminum magnesium silicate. The most preferred silica flow conditioner is silicon dioxide.

  Examples of stabilizers include gum arabic, albumin, polyvinyl alcohol, alginic acid, bentonite, calcium hydrogen phosphate, carboxymethylcellulose, hydroxypropylcellulose, colloidal silicon dioxide, cyclodextrins, glyceryl monostearate, hydroxypropylmethylcellulose, three Magnesium silicate, magnesium aluminum silicate, propylene glycol, propylene glycol alginate, sodium alginate, carnauba wax, xanthan gum, starch, stearate (s), stearic acid, stearic monoglyceride and stearyl alcohol. The most preferred stabilizer is magnesium trisilicate.

  In a preferred embodiment of the present invention, the novel fast acting dictin formulation core includes the following components: about 4-10% by weight, most preferably about 7% by weight pyridoxine hydrochloride; about 4-10% by weight. Most preferably about 7% by weight doxylamine succinate; about 40-80% by weight, most preferably about 62% by weight microcrystalline cellulose; about 10-30% by weight, most preferably about 18% by weight About 0.5-5 wt.%, Most preferably about 1 wt.% Silicon dioxide; about 0.5-5 wt.%, Most preferably about 3 wt.% Croscarmellose sodium; and about 0.5 wt. ~ 5 wt%, most preferably about 3 wt% magnesium stearate.

Example 1
An example of a 145 mg dictin fast acting formulation core formulation is shown below.

  An enteric coating is applied to the core composed of the above ingredients using an aqueous enteric coating that allows the formulation to pass through the stomach relatively intact and quickly dissolve in the intestine.

  For coating, the following coating formulation is employed.

  The purpose of the seal coating is to provide a smooth surface for the enteric coating, thereby preventing bulging, dents or crevices in the core surface that results in enteric coating unevenness.

Dissolution data The above-mentioned fast-acting formulation was measured in the following Table 3 when measured at 100 ° C. per minute using a type 2 dissolution test apparatus at 37 ° C. in 1000 ml of pH 6.8 phosphate buffer. In vitro elution characteristics were shown. The numerical value is the percentage of the amount of active ingredient eluted relative to the amount of active ingredient contained in the fast acting formulation at the start of the test.

  It can be explained that the extremely low dissolution rate after 5 minutes seen in Runs 1 to 3 is due to the fact that the core formulation did not disintegrate in 5 minutes.

Example of Manufacturing Method The formulation of the present invention was prepared using the ingredients shown in Table 1 above. A pre-blend is obtained by mixing doxylamine succinate and silicon dioxide listed in National Drug Collection (NF) in a 2 cubic foot V-Blender. The resulting pre-blend is pulverized with a Quadro Co pulverizer model 196S with a 40 mesh sieve.

  Pyridoxine hydrochloride is also pulverized by a Quadro pulverizer model 196S with a 40 mesh sieve. Thereafter, the pulverized pyridoxine hydrochloride was mixed with a pre-blend of doxylamine and silicon dioxide listed in National Drug Collection.

  The microcrystalline cellulose is crushed and sieved through a 40 mesh screen and then roughly bisected. Half of the microcrystalline cellulose is combined with the pre-blend containing the two active ingredients prepared above in 650 L Gallay Bin and the remaining half of the microcrystalline cellulose is added thereto. The ingredients filled in galeibin were mixed to obtain a blend, to which magnesium trisilicate and croscarmellose were added, and the newly obtained mixture was further mixed. Finally, magnesium stearate is added and further mixed to obtain the final blend, completing the preparation of the core formulation.

  The final blend is compressed into a tablet form, followed by a seal coating, an enteric coating using a commercially available aqueous enteric coating, and a surface coating for cosmetic purposes. The whole manufacturing process is shown in FIG.

All coating steps using the ingredients in Table 2, namely the seal coating to enter the core, the enteric coating and the coating with Opadry White (colored coating) are all Vector Hi ^™ coating pans (Vector Hi) equipped with a peristaltic pump. ^TM coater pan) can be advantageously carried out.

Example 2
Another example of a 146 mg dictin fast acting formulation core formulation is shown below. The prescription for the core was produced in the same manner as in Example 1 above. This example shows that the rapid efficacy of the formulations of the present invention can also be obtained with different excipient groups.

  For coating, the following coating formulation is adopted.

  The fast-acting formulation of Example 2 was measured in the following Table 6 when measured under conditions of 100 revolutions per minute using a type 2 dissolution test apparatus at 37 ° C. in 1000 ml of pH 6.8 phosphate buffer. In vitro elution characteristics were shown. The numerical value is the percentage of the amount of active ingredient eluted relative to the amount of active ingredient contained in the fast acting formulation at the start of the test.

  From these results, it was found that the novel formulation has a rapid effect as shown in the dissolution characteristics. The average dissolution rate of pyridoxine hydrochloride exceeds 90% within 120 minutes from the start of the test. Similarly, the average dissolution rate of doxylamine succinate exceeds 90% within 120 minutes from the start of the test.

Example 3 (Comparative example using a conventional formulation)
Shown below is an example of a prior art dictin formulation. One tablet is provided as 146.2 mg tablets. It can be seen that the formulation of this example is remarkably slow in its dissolution characteristics compared to the formulation of the present invention.

  For coating, the following coating formulation is adopted.

  The currently used formulation shown in Example 3 was measured in a 1000 ml phosphate buffer solution at pH 6.8 at 37 ° C. using a type 2 dissolution test apparatus at 100 rpm. The in vitro dissolution characteristics of Table 9 below were shown. The numerical value is the percentage of the amount of active ingredient eluted relative to the amount of active ingredient contained in the fast acting formulation at the start of the test.

  From these results, the conventional formulation shows a significantly delayed dissolution pattern as compared with the novel formulation of the present invention. In fact, on average after 90 minutes, only 60% of doxylamine and 67% of pyridoxine hydrochloride were eluted. Slow in vitro dissolution characteristics indicate slow release. As demonstrated in Examples 1 and 2, the new formulation has a remarkably fast-release dissolution profile, which provides a fast-acting effect. New formulations overcome many, if not all, of the disadvantages associated with the prior art.

  The terms and descriptions used herein are merely illustrative of preferred embodiments of the invention and are not intended to limit the many variations that those skilled in the art will appreciate in practicing the invention. All modifications of the present invention, whether known or not, that do not directly affect the function of the present invention are also encompassed by the claims of this application.

FIG. 1 is a diagram comparing the dissolution characteristics of two examples of the fast-acting formulation of the present invention with the dissolution characteristics of a prior art formulation. In the dissolution characteristics (Example 1) of the fast-acting formulation shown at the beginning, almost 100% of the two active ingredients were released within 45 minutes. Even the dissolution characteristics of the fast-acting formulation shown second (Example 2), about 95% of the two active ingredients were released within 120 minutes. Finally, the dissolution characteristics (prior art) of currently available formulations, shown for comparison, released about 100% pyridoxine hydrochloride and about 90% doxylamine succinate within 240 minutes. FIG. 2 is a flowchart showing an outline of a preferred production method for producing a preferred formulation of the present invention.

Claims (18)

A fast-acting formulation of pyridoxine hydrochloride and doxylamine succinate having an enteric coating, containing a disintegrant, and in a 1,000 ml phosphate buffer solution at pH 6.8, using a type 2 dissolution test apparatus at 37 ° C A fast-acting prescription that satisfies the following elution characteristics (a) to (d) when measured under conditions of 100 revolutions per minute.
(A) At 30 minutes after the start of the test, at least 40% of the total amount of pyridoxine hydrochloride and doxylamine succinate elutes;
(B) At 60 minutes after the start of the test, at least 70% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes;
(C) At 90 minutes after the start of the test, at least 80% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes;
(D) At 120 minutes after the start of the test, at least 90% of the total amounts of pyridoxine hydrochloride and doxylamine succinate are eluted. The following elution characteristics (a) to (c) are satisfied when measured under conditions of 100 revolutions per minute using a type 2 elution test apparatus at 37 ° C. in 1000 ml of pH 6.8 phosphate buffer. The rapid-acting prescription according to claim 1.
(A) At 15 minutes after the start of the test, at least 20% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes;
(B) at least 60% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate at 45 minutes after the start of the test;
(C) At 75 minutes after the start of the test, at least 80% of the total amount of each of pyridoxine hydrochloride and doxylamine succinate elutes. Pyridoxine hydrochloride and doxylamine succinate within 5 minutes from the start of the test when measured under conditions of 100 rpm per minute using a type 2 dissolution test apparatus at 37 ° C. in 1000 ml of pH 6.8 phosphate buffer The fast-acting formulation according to claim 1 or 2, wherein at least 40% of the total amount of each is eluted. Having a core with an enteric coating consisting of at least one layer, the core being stable with pyridoxine hydrochloride, doxylamine succinate, and as an inactive excipient, a bulking agent or binder, a disintegrant, a lubricant, a silica flow conditioner The rapid-acting prescription according to claim 1 or 2, comprising an agent. The rapid-acting formulation according to claim 4, wherein the extender or binder is composed of microcrystalline cellulose. The rapid-acting prescription according to claim 4, wherein the disintegrant is composed of croscarmellose sodium. The fast-acting formulation according to claim 4, wherein the lubricant is composed of magnesium stearate. The rapid-acting prescription according to claim 4, wherein the silica flow conditioner is composed of silicon dioxide. The fast-acting formulation according to claim 4, wherein the stabilizer is composed of magnesium trisilicate. The fast-acting prescription according to claim 1 or 2, wherein the core includes the following (a) to (g).
(A) 4-10% by weight of pyridoxine hydrochloride;
(B) 4-10% by weight of doxylamine succinate;
(C) 40-80% by weight of microcrystalline cellulose;
(D) 10-30% by weight of magnesium trisilicate;
(E) 0.5-5% by weight silicon dioxide;
(F) 0.5-5% by weight croscarmellose sodium; and (g) 0.5-5% by weight magnesium stearate. The rapid-acting formulation according to claim 10, wherein the core includes the following (a) to (g).
(A) 7% by weight of pyridoxine hydrochloride;
(B) 7% by weight of doxylamine succinate;
(C) 62% by weight of microcrystalline cellulose;
(D) 18% by weight magnesium trisilicate;
(E) 0.7% by weight silicon dioxide;
(F) 2.5% by weight croscarmellose sodium; and (g) 2.8% by weight magnesium stearate. The fast-acting formulation according to claim 4, wherein the enteric coating comprising at least one layer is formed from an aqueous raw material. The enteric coating comprising at least one layer is composed of a seal coating that covers the core, an authentic enteric coating that covers the seal coating, and a cosmetic coating that covers the true enteric coating. The rapid-acting prescription according to claim 12. The rapid-acting prescription according to claim 1 or 2, which is a prescription for alleviating symptoms of mammalian nausea and vomiting. The rapid-acting prescription according to claim 1 or 2, which is a prescription for relieving symptoms of nausea and vomiting during human pregnancy. A drug for alleviating symptoms associated with nausea and vomiting, comprising the prescription of claim 4. A method for producing the fast-acting formulation according to claim 4, comprising the following steps.
-Mixing doxylamine succinate and silica flow conditioner to obtain a pre-blend;
Mixing the preblend with pyridoxine hydrochloride to obtain an active ingredient blend;
Mix the active ingredient blend with inactive excipients bulking agent or binder, disintegrant, lubricant and stabilizer to obtain the final blend; and • Tablet and coat the final blend. The final tableting and coating step includes compressing the final blend into a tablet shape, applying a seal coating to the resulting tablet shape, then applying an enteric coating, and then applying a colored coating. The method of claim 17.

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