Patent Application
20180116967
The present invention is directed to a cyclobenzaprine-containing extended-release pharmaceutical composition in a direct compression tablet, and methods of preparing the same.
Flexeril® is an immediate-release tablet containing cyclobenzaprine hydrochloride as the active agent, which has been approved by the U.S. Food and Drug Administration (FDA), that is used to cause a relaxing effect on skeletal muscles. The tablet is formed by mixing cyclobenzaprine hydrochloride with lactose, starch, magnesium stearate, and pigment, forming a tablet, and coating the tablet with a soluble coating. After oral administration of a 10-mg tablet, the average bioavailability of cyclobenzaprine is estimated to be 33% to 55%. About 93% of the drug is coupled to plasma protein.
The chemical name of cyclobenzaprine (which was first synthesized in 1961) is 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, and it has the structural formula depicted below as formula I.
It is well known that the drug is released quickly when an immediate-release cyclobenzaprine hydrochloride tablet is administered to patients with muscle spasms. Therefore, to maintain an effective pharmaceutical plasma concentration within the range needed to obtain the desired therapeutic effect, the immediate-release tablet is usually administered many times a day, which causes significant fluctuation in the drug's plasma concentration. For example, a 5 mg dose of the Flexeril® tablet (or increased to a 10 mg dose) administered 3 times/day is needed to show any relaxation effects.
According to clinical research, wherein a control group is referenced, and from information obtained from post marketing surveillance programs, it is known that the administration of cyclobenzaprine has serious adverse effects. According to the report of Borenstein D. G. et al. (Clinical Therapeutics, 2003, 25(4): 1056-1073), sedation side effects often occur when immediate-release cyclobenzaprine tablets are administered 3 times a day.
Extended-release dosage forms provide advantages compared to the immediate-release dosage forms. For example, extended-release dosage forms decrease variations in the plasma concentration-time profile, so as to reduce the side-effects often associated with immediate release dosage forms, thereby increasing patient compliance and therapeutic efficacy.
Cyclobenzaprine has a chemical structure that is similar to tricyclic antidepressants (TCA), which are known to exhibit adverse effects. Common adverse effects exhibited by cyclobenzaprine are, for example, drowsiness and thirst. For the elderly, myocardial infarction, glaucoma, arrhythmia, heart conduction interference, heart block, and heart failure can occur, and adverse events such as prolongation of the QT interval in the electrocardiogram and intraocular pressure can occur. Therefore, AMRIX®, an extended-release cyclobenzaprine formulation, formulated as an extended-release capsule filled with cyclobenzaprine-containing granules was marketed in 2007.
A. J. Weil et al. (Postgraduate Medical Journal, 2010 July; 122(4): 158-169) reported that most active agents show mild to moderate adverse reactions. The highest rate of adverse event occurrence for cyclobenzaprine occurs with the immediate release dosage form. Adverse event occurrence is 48.8% for the immediate-release dosage form, 39.7% for the 30-mg extended-release dosage form, 38.6% for the 15-mg extended-release dosage form, and 28.1% for placebo. The most common adverse event is thirst, where the incidence rate is 5.5% for the 15-mg extended-release dosage form, 13.5% for the 30-mg extended-release dosage form, 13.8% for the immediate-release dosage form, and 1.6% for placebo. Drowsiness is another common adverse event, wherein the incidence rate for patients with significant drowsiness is 7.3% for administration of the immediate-release tablet, 0.8% for the 15-mg extended-release dosage form, and 1.6% for the 30-mg extended-release dosage form.
U.S. Pat. Nos. 7,387,793 and 7,790,199 disclose multi-particulate beads that are an immediate-release particle core of cyclobenzaprine coated with a water insoluble polymer or a mixture of a water insoluble polymer and a small amount of a water soluble polymer. The water insoluble polymer can be cellulose acetate, polyvinyl acetate, Eudragit®, etc.
U.S. Patent Publication No. 2012/0064164 discloses an extended-release pharmaceutical composition that is a core coated with a layer of cyclobenzaprine that is then coated with one or more layers of an extended-release agent. Alternatively, cyclobenzaprine and the extended-release agents are mixed together and then coated onto the core to produce the extended-release particles. The water insoluble extended-release agent(s) provides the extended-release effect.
Korean Patent Publication No. 20120091748 discloses an extended-release pharmaceutical composition of cyclobenzaprine. The publication emphasizes that glyceryl behenate must be added when preparing the tablets, which also include ethyl cellulose and organic acids.
In view of the prior art, the inventors developed the present invention “Extended Release Tablet of Cyclobenzaprine.” The summary of the present invention is provided below.
After studying commercial products and the literature, it can be seen that an extended-release dosage form of cyclobenzaprine is advantageous in that it can reduce the adverse effects that are commonly associated with immediate-release dosage forms of cyclobenzaprine. The present invention provides an extended-release tablet containing cyclobenzaprine that is easier and more cost effective to manufacture than prior art-known extended-release dosage forms. In particular, the tablet of the invention avoids the disadvantages associated with coated extended-release dosage forms, such as granule disintegration, coating inefficiency, and the need for solvent recycling.
One aspect of the present invention is an extended-release cyclobenzaprine-containing tablet that is made by direct compression. The term cyclobenzaprine, as used herein, means cyclobenzaprine or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the cyclobenzaprine is present as cyclobenzaprine hydrochloride. The tablet includes excipients such as an extended-release matrix forming material, a filler, a lubricant, and a glidant.
Another aspect of the present invention is an extended-release tablet composition made by direct compression that includes dantrolene sodium, methocarbamol, metaxalone, carisoprodol, diazepam or a pharmaceutically acceptable salt, solvate, and/or ester thereof. The tablet includes excipients, such as an extended-release matrix, a filler, a lubricant, and a glidant. The extended-release tablet is essentially the same as the cyclobenzaprine-containing tablet, but replaces the cyclobenzaprine with dantrolene sodium, methocarbamol, metaxalone, carisoprodol, diazepam, or a pharmaceutically acceptable salt, solvate and/or ester thereof.
The dissolution profile of the tablet is tested using United States Pharmacopeia (USP) dissolution apparatus I wherein the dissolution test is carried out in 900 mL of 0.1 N HCl at 37° C. and using a rotation speed of 50 rpm. The extended-release tablet exhibits a dissolution profile wherein about 30%-45% of active agent (preferably cyclobenzaprine) is released within 2 hours, about 45%-70% of active agent is released within 4 hours, and more than about 65% of the active agent is released within 8 hours.
In another aspect of the present invention, the extended-release tablet does not include an extended-release coating (film). It also is not necessary to include organic or inorganic acids or glyceryl behenate as a component of the extended-release tablet. In one embodiment, the extended-release tablet does not include organic or inorganic acids or glyceryl behenate.
Another aspect of the present invention is a method of preparing the cyclobenzaprine-containing extended-release tablet. The method involves: (i) homogenously mixing cyclobenzaprine or a pharmaceutically acceptable salt and/or solvate thereof with an extended-release matrix material, a filler, and a glidant to form a first mixture; (ii) homogenously mixing a lubricant with the first mixture to form a second mixture; and (iii) directly compressing the second mixture to form the extended-release tablet. It is not essential to add organic solvents, aqueous solvents, distilled water, or organic acids in any step of the process. The method is simple and cost effective.
The extended-release cyclobenzaprine tablet exhibits release of the cyclobenzaprine for between 8-12 hours when subjected to dissolution testing in 900 mL of 0.1 N HCl at 37° C. and a rotation speed of 50 rpm using USP dissolution test apparatus I.
The dissolution profiles depicted in the figures were determined in 900 mL of 0.1 N HCl at 37° C. and a rotation speed of 50 rpm using USP dissolution test apparatus I.
Common methods for preparing tablets include wet granulation, dry granulation, and direct compression. In wet granulation, the active agent is combined and mixed with excipients (such as fillers, the glidants, and binders) in the presence of a solvent (typically water) to provide a mixture; the mixture is then dried and pulverized to provide granules; and the resulting granules, optionally combined with additional excipients, is compressed into a tablet. Because water or organic solvents are used during the preparation, heating or another drying method is needed. In dry granulation, the active agent is combined and mixed with excipients; the resulting mixture compacted and pulverized to provide granules, and the resulting granules, optionally combined with additional excipients, compressed into a tablet. Although water or organic solvents and the heating or drying step are excluded, compression and pulverization are still needed to form granules. In the direct compression process, the active agent is simply combined and mixed with various excipients and the resulting mixture directly compressed into a tablet.
The physical characteristics of a tablet, such as hardness, uniformity, disintegrative ability, and in vitro dissolution and, thus, the tablets efficacy as a therapeutic agent, are affected, in unpredictable ways, by the method of making the tablet and the selection of excipients.
The method of making the extended-release tablet of the present invention involves homogenously mixing the active agent with the excipients to provide a mixture and directly compressing the mixture into a tablet. The excipients may be sieved either individually or as a mixture before and/or after being combined with the active agent.
The method advantageously avoids mixing the active agent with solvents, in particular, organic solvents. When organic solvents are used, there may be residual organic solvent left in the final product. See Technical Guideline No. [H]GPH7-1 entitled “The technical guidelines for the studies on residual solvents in a chemical drug” published by the China Food and Drug Administration. The residual solvents can directly affect the quality and safety of the final product. Many organic solvents are harmful to the environment and to humans. In one aspect of the present invention the cyclobenzaprine-containing extended-release tablet is substantially free of organic solvents, and in another aspect is substantially free of solvents. The term “substantially free,” as used herein, means less than 10,000 ppm, preferably less than 1,000 ppm, and more preferably less than 100 ppm.
The filler used in the method of the invention can be lactose, spray-dried lactose, mannitol, or a combination thereof. Spray-dried lactose, which has good fluidity and compressibility and exhibits good stability high even if stored in humid conditions, is a preferred filler. The glidant can be silica, peptized silica, or a combination thereof. There are many pharmacologically acceptable silica products. Peptized silica (e.g., Aerosil® 200) is a preferred glidant. The lubricant can be magnesium stearate. Hydroxypropyl methylcellulose (HPMC) is a preferred extended-release matrix material and can be, for example, 90SH-4000SR (HPMC 4000) or 90SH-15000SR (HPMC 15000).
In one embodiment, the release profile of the extended-release tablet of the invention does not deviate from the release profile exhibited by the commercially available extended-release cyclobenzaprine dosage form Amrix® ER by more than about 10% over 2 to 16 hours.
Table 1 summarizes the release profile exhibited by suitable and unsuitable dosage forms in 900 mL of 0.1 N HCl at a temperature of 37° C. and a rotation speed of 50 rpm using USP apparatus.
The dosage form releases about 30 to 45% over 2 hours, about 45 to 70% over 4 hours, and more than about 65% over 8 hours. Preferably, the dosage form releases about 30 to 45% over 2 hours, about 45% to 60% over 4 hours, and more than 70% over 8 hours. More preferably, the dosage form releases 32.2 to 36.6% over 2 hours, 51.0 to 58.2% over 4 hours, and 74.5 to 82.4% over 8 hours. If the amount released over 8-hours is less than 48.3%, the dosage form is determined as unacceptable.
A preferred composition of the cyclobenzaprine-containing extended-release tablet of in the present invention is provided in Table 2. The composition is prepared by accurately weighing the excipients lactose, silica, hydroxypropyl methylcellulose, and magnesium stearate; homogenously combining the excipients with the cyclobenzaprine to provide a mixture, and directly compressing the mixture to provide a tablet. Optionally, the excipients are sieved either individually and/or in combination and before or after being combined with the cyclobenzaprine. The tablet is formed by direct compression. The extended-release tablet can contain cyclobenzaprine in an amount of about 220-250 mg per tablet, wherein the amount of cyclobenzaprine is about 6% (w/w) to about 14% (w/w) of the total weight of the tablet; the amount of lactose is about 5% (w/w) to about 80% (w/w), preferably about 9% (w/w) to about 70% (w/w) of the total weight of the tablet, and more preferably about 35% (w/w) to about 65% (w/w) of the total weight of the tablet, e.g., 45% (w/w) to 65% (w/w) or 50% (w/w) to 65% (w/w) of the total weight of the tablet; the amount of hydroxypropyl methylcellulose is about 15% (w/w) to about 85% (w/w), preferably about 20% (w/w) to about 81% (w/w) of the total weight of the tablet, more preferably about 25% (w/w) to about 55% (w/w) of the total weight of the tablet, e.g., 20% (w/w) to 40% (w/w) or 25% (w/w) to 35% (w/w) of the total weight of the tablet; and the amount of silica (preferably peptized silica) is about 0.5% (w/w) to 2% (w/w) of the total weight of the tablet, preferably about 0.9% (w/w) of the total weight of the tablet; and the amount of lubricant (preferably magnesium stearate) is about 0.5% (w/w) to 3.5% (w/w), preferably about 1.3% (w/w) of the total weight of the tablet.
The preferred method of making the extended-release tablet of the present invention involves (a) combining and homogenously mixing the cyclobenzaprine, spray-dried lactose, hydroxypropyl methylcellulose, and peptized silica to provide a first mixture, (b) combining and homogenously mixing magnesium stearate with the first mixture to provide a second mixture, and (c) directly compressing the second mixture into a tablet. The components of the tablet are accurately weighed before being combined. The components of the tablet may be sieved individually and/or in combination before or after being combined with the cyclobenzaprine.
The ratio of filler (preferably) lactose to extended-release matrix forming material (preferably hydroxypropyl methylcellulose) influences the release profile of the tablet. The formulae of Tablets 06-09 are shown in Table 3. The total amount of lactose and hydroxypropyl methylcellulose in each formula is about 90% of the total weight of the tablet. When the amount of hydroxypropyl methylcellulose in the total weight of the tablet is decreased from 81.81% to 50.00%, the amount of lactose in the total weight of the tablet is simultaneously increased from 9.09% to 40.91%. Table 4 and
The amount of lactose in Tablets 08-09 is 9.09%-40.91% of the total weight of the tablet. The amount of lactose in Tablet 16 is 56.82% (shown in Table 5), but that of hydroxypropyl methylcellulose is less than any one of Tablets 06-09.
Referring to Table 5, which shows the formulae of Tablets 10-13 and 16, the total amount of lactose and hydroxypropyl methylcellulose is 90.41% of the total weight of the tablet. Table 7 and
The amount of lactose in Tablet 10 is similar to the amount of hydroxypropyl methylcellulose. In Tablets 11, 16, 12, and 13 the amount of lactose is increased and that of hydroxypropyl methylcellulose is simultaneously decreased. As shown in Table 6, the ratio of HPMC:lactose is 33.33% in Tablet 06, 66.67% in Tablet 07, 11.11% in Tablet 08, 81.82% in Tablet 09, 122.22% in Tablet 11, 166.68% in Tablet 16, 207.69% in Tablet 12 and 344.44% in Tablet 13. Comparing the dissolution profile of Tablets 10-13 and 16 in
The total amount of lactose and hydroxypropyl methylcellulose in each of Tablets 8, 13, and 16 is about 90%. As depicted in
The HPMC in Tablet 12 was replaced with different celluloses as the extended-release matrix material to provide Tablets 27-29 so as to evaluate how different celluloses affect the dissolution profile of the cyclobenzaprine. The formulae of Tablets 27-29 is provided in Table 8. As shown in Table 8, low-substituted hydroxypropyl cellulose (L-HPC) is used in Tablet 27, ethylcellulose is used in Tablet 28, and hydroxypropyl methylcellulose (HPMC) 15000 is used in Tablet 29. The components in each formula are directly compressed into tablets using the above described method.
As shown in Table 9 and
Table 10 shows the formulae of Tablets 01-03, which contain glyceryl behenate. Tablets 01-03 were found to be unsuitable as an extended-release tablet because they exhibited insufficient hardness and disintegrated too easily. Tablet 03 also exhibited capping.
Table 11 shows the formulae of Tablets 17, 18, and 21, which include citric acid. The combined amount of lactose, citric acid, and hydroxypropyl methylcellulose in Tablets 17, 18, and 21 are 91.48%, 90.92%, and 90.91% of the total weight of the tablet, respectively.
The amount of lactose and hydroxypropyl methylcellulose in Tablet 16 is 56.82% and 34.09% of the total weight of the tablet, respectively. The amount of lactose and hydroxypropyl methylcellulose in Tablet 12 is 61.36% and 29.55% of the total weight of the tablet, respectively. The amounts of lactose and hydroxypropyl methylcellulose in Tablet 18 is 56.82% and 34.09% of the total weight of the tablet, respectively. The amount of lactose and hydroxypropyl methylcellulose in Tablet 21 is 59.09% and 29.55% of the total weight of the tablet, respectively. Thus, the amount of lactose and hydroxypropyl methylcellulose in the citric acid-containing tablets of Examples 18 and 21 are similar to the amounts in citric acid-free tablets 16 and 12.
As shown in
If desired, the tablets described above can further include a coating, such as a sugar coating or other non-functional film coating, to form a sugar coated tablet or film coated tablet. The coating can be applied using art-known methods for coating tablets. For example, a film coated Tablet 14 is formed by compressing the materials to form Tablet 12 and then coating the resulting tablet with film coating solution I. In addition, a film coated Tablet 15 is formed by compressing the materials to form Tablet 12 and then coating the resulting tablet with film coat solution II. The term “non-functional film coating” means a coating that does not cause extended-release of the active agent. Non-functional film coatings are typically used to simply improve the appearance of the tablet.
The difference between the film coat solution I and the film coat solution II is that hydroxypropyl methylcellulose (HPMC 606) is dissolved in alcohol in the former, and all components of the film coat are dissolved in the distilled water in the latter. In addition, the composition of the film coat solution I includes hydroxypropyl methylcellulose phthalate (HP-55), which is absent in the film coat solution II. Other differences between the compositions are shown in Table 12, wherein the amounts of titanium dioxide and yellow iron sesquioxide in the film coat solution II are slightly lower than the film coat solution I.
The film coat solution I is prepared by combining 3.5 g hydroxypropyl methylcellulose (HPMC 606) dissolved in 104 mL of 95% alcohol, 1.5 g polyethylene glycol 6000 (PEG 6000) dissolved in 26 mL distilled water, 9 g hydroxypropyl methylcellulose phthalate (HPMCP, HP-55) dissolved in 50 mL distilled water to provide a solution, and adding 0.77 g titanium dioxide and 0.2 g yellow iron sesquioxide to the solution.
The film coat solution II is prepared by combining 3.5 g hydroxypropyl methylcellulose (HPMC 606) and 1.5 g polyethylene glycol 6000 (PEG 6000) in 50 mL distilled water, and adding 0.38 g titanium dioxide and 0.1 g yellow iron sesquioxide.
The film coated Tablet 14 is formed by compressing the materials to form tablet 12 followed by applying film coating solution I. The film coated Tablet 15 is formed by the same process except that film coating solution I is replaced by film coating solution II. As shown in Table 13 and
The term “about” when associated with a range for a value means that the upper and lower limits of the range are approximate and are not limited to a expressly recited value. In other words, the range includes values slightly higher or lower than the expressly recited limits without departing from the scope of the present invention. The term “about,” as used in the specification, will be readily understood by a person of ordinary skill in the art. If the term “about” would not be readily understood by a person of ordinary skill in the art, the term “about” may be taken to mean the expressly recited value±10%.
The terms “drug”, “active component”, “active agent”, “main drug component”, “main active component” and the like mean a component, such as a compound, an antibody, a protein, or the like, that has an effect on physiological activity. These terms are interchangeable, and their meanings are the same.
The terms “extended-release”, “slow release” and so on have their art-recognized meaning, are interchangeable, and have the same meaning. The terms “free of solvent or solvent mixture” and “free of solvent” mean that the process for preparing a tablet does not use organic solvents, aqueous solvents, or solvent mixtures.
The terms “excipient” or “pharmaceutically acceptable carrier or excipient” and “bioavailable carrier or excipient” mean any components, other than the active agent, included in the tablets. These components include, for example, known excipients such as, dispersants, coatings, preservatives, and delayed absorbents. In general, the carrier or the excipient themselves do not exhibit any therapeutic efficacy. Preferably, the pharmaceutically acceptable carrier or excipient when administered to an animal or human does not result in a reaction, allergic response, or other undesirable effect.
In summary, all technical and scientific terms in the specification have their common meaning as would be readily understood by a person of ordinary skill in the art unless the term is otherwise defined. The present invention will now be described more specifically with reference to the following Examples, which are illustrative and not intended to be limiting. The active agents and materials used in the present invention are commercially available.
The present invention is an extended-release cyclobenzaprine-containing tablet, wherein cyclobenzaprine or a pharmaceutically acceptable salt and/or solvate, thereof is combined with an extended-release matrix material, a filler, a glidant and a lubricant. The tablet is prepared by homogenously mixing the components, without adding organic solvents, aqueous solvents, distilled water, or organic acids, to provide a mixture, and directly compressing the resulting mixture into the extended-release tablet.
The present invention can be realized by the following Examples, and can be accomplished by a person of ordinary skill in the art according to the disclosure. The following Examples, however, are illustrative and are not intended to be limiting.
An extended-release tablet is prepared by (a) accurately weighing cyclobenzaprine, lactose, hydroxypropyl methylcellulose 90SH-4000SR, and peptized silica, and homogenously mixing and sieving the components to provide a first mixture; (b) sieving magnesium stearate and homogenously mixing the magnesium stearate with the first mixture to provide a second mixture, and then sieving the second mixture; and (c) directly compressing the second mixture into tablets. The method does not use any organic solvents, aqueous solvents, or distilled water. The dissolution rate of the resulting tablet in 900 mL of 0.1N HCl at 37° C. and a rotation speed of 50 rpm using USP apparatus I is similar to that of the commercial product (Amrix® ER capsules).
The tablets of Examples 2 (tablets 06-09) are prepared using the method described in Example 1.
The tablets of Examples 3 (tablets 10-13) are prepared using the method described in Example 1.
The tablets of Example 4 (tablets 16 and 19) are prepared using the method described in Example 1.
An extended-release tablet including components in the amounts listed in the table above is prepared by (a) homogenously mixing cyclobenzaprine, lactose, citric acid, hydroxypropyl methylcellulose 90SH-4000SR and peptized silica and sieving the components to provide a first mixture; (b) sieving magnesium stearate and homogenously mixing the magnesium stearate with the first mixture to provide a second mixture, and then sieving the second mixture; and (c) directly compressing the second mixture into tablets.
An extended-release tablet having components in the amounts listed in the table above is prepared by (a) homogenously mixing cyclobenzaprine, lactose, glyceryl behenate, hydroxypropyl methylcellulose 90SH-4000SR and peptized silica and sieving the components to provide a first mixture; (b) sieving magnesium stearate and homogenously mixing the magnesium stearate with the first mixture to provide a second mixture and then sieving the second mixture; and (c) directly compressing the second mixture into tablets. It is found that the hardness of the resulting tablet formed by direct compression is unsatisfactory, and thus the tablet is unsuitable.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201510961159.4 | Dec 2015 | CN | national |
This application is a continuation-in-part of International Application No. PCT/CN2016/110395, filed Dec. 12, 2016, now pending, the entire contents of which are expressly incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CN2016/110395 | Dec 2016 | US |
| Child | 15860330 | US |
