TWI600425B - Extended release tablet of cyclobenzaprine - Google Patents

Description

Extended release dosage form of cyclobenprazole

The present invention relates to a pharmaceutical composition comprising cyclobenzine as a main component, which is prepared by mixing the main component and the excipient, and is suitable for use in a delayed release dosage form for the treatment of muscle relaxants or skeletal muscle disorders.

By the FDA (Food and Drug Administration, FDA) approved a main component comprising benzyl ring Princeton hydrochloride (cyclobenzaprine hydrochloride), skeletal muscle relaxants, presents the activity of a system Flexeril ^® immediate release tablets. The tablet is a tablet made of cyclic benzidine hydrochloride and lactose, starch, magnesium stearate, and a pigment. The water-soluble, pharmaceutically acceptable excipient is then applied as a coated lozenge. Oral administration of 10 mg of lozenge, the average bioavailability of cyclobenpramine after absorption is estimated to be 33% to 55%. Approximately 93% of the drug binds to plasma proteins.

The chemical formula of cyclobenzine is 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propylamine (3-(5H-Dibenzo[a , d] cyclohepten-5-ylidene)-N, N-dimethyl-1-propanamine), which has the structural formula of Formula I, was first synthesized in 1961.

It is well known that in most patients with muscle spasm, immediate-release tablets of cyclomethalin hydrochloride lozenges provide rapid release of the drug. Therefore, in order to maintain an effective drug concentration within the therapeutic range to achieve the desired therapeutic effect, it is usually necessary to administer this type of drug multiple times per day in order to seek significant fluctuations in drug concentration. For example, Flexeril ^® tablets can be soothed by 5 mg or 3 mg per day for 3 times a day.

In the clinical study of the establishment of the control group, as well as the information of the Post Marketing Surveillance Program, it was learned that there were some serious serious adverse effects associated with the administration of cyclobenzine. According to Borenstein D.G. et al., 2003, Clinical Therapeutics, Vol. 25, No. 4, pp. 1056-1073, three times a day, cycloheximide immediate release tablets are administered, and seization often occurs.

The extended release formulation (extended release formulation) provides some advantages over the immediate release dosage form. Extended release dosage forms reduce the plasma concentration-time profile of the Peak-trough Fluctuation period, thereby reducing fluctuation-related side effects and/or lowering the effects of treatment concentration fluctuations, thereby increasing Patient compliance and treatment efficacy. In addition, extended release formulation formulations can be used in drug development using standard rapid release formulation formulations to compensate for the inability to exhibit pharmacokinetic properties.

Since the chemical structural formula of cyclobenpramine is similar to that of tricyclic antidepressants (TCAs), antidepressants are known to exhibit sedative adverse effects. Common uncomfortable phenomena are somnolence and dry mouth. . For geriatric diseases, even myocardial infarction, glaucoma, arrhythmia, interference with cardiac conduction, heart block, heart failure, and prolonged ECG QT Interval, Intraocular Pressure and other undesirable phenomena . Therefore, the AMRIX R ^® marketed in 2007 is a multi-granule type extended release capsule.

Weil A. J. et al., 2010, Postgraduate Medical Journal, Vol. 122, No. 4, pp. 158-169, reported that most of the related preparations exhibited mild to moderate adverse effects. The overall incidence of adverse events was higher at 48.8% for the immediate release lozengeline, followed by 39.7% for the 30 mg extended release dosage form, 38.6% for the 15 mg extended release dosage form and 28.1% for the placebo. The most common adverse event, the incidence of dry mouth was 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 tablet, and 1.6% for the placebo. Drowsiness is another common anomaly. The incidence of immediate release tablets is 7.3% for the more obvious patients, 0.8% for the 15 mg extended release dosage form, and 1.6% for the 30 mg extended release dosage form.

The multi-particulate pharmaceutical dosage beads disclosed in U.S. Patent Nos. 7,387,793 and 7,790,199, each of which incorporates a water-insoluble polymer or a small amount of a water-soluble polymer to form a functional film for packaging A core particle is coated to form the extended release granule; the core particle is an immediate release cyclic benzyl chloride particle. The water-insoluble polymer may be Cellulose Acetate, Polyvinyl Acetate, methacrylate copolymer acrylic resin (Eudragit) or the like.

U.S. Patent No. 20120064164 discloses a delayed release pharmaceutical composition having a core which is first coated with a layer of cyclic benzide drug and then coated with one or more extended release agents; or after mixing the drug with the extended release agent It is applied to the core to produce a delayed release granule; it is a water-insoluble extended release agent to achieve an extended release effect.

Korean Patent No. 20120091748 discloses a cyclic benzylproton extended release pharmaceutical composition, in which it is particularly emphasized that glyceryl behenate must be added when preparing a tablet using ethyl cellulose or an organic acid.

In view of the deficiencies in the prior art, the applicant of the case, after careful experimentation and research, and a spirit of perseverance, finally conceived the invention of the invention, "extended release dosage form of benzalben", and To overcome the shortcomings of the prior art, the following is a brief description of the case.

Upon investigation of commercial or literature information, it is known that the extended release dosage form of cyclobenprazole can improve the common undesirable phenomena of immediate release of cyclobenprazole dosage form. For example, the extended-filled granule-filled capsule dosage form requires consideration of the mechanical properties of the granules, the coating material, and the like, which are sufficient to affect the particle collapse, the coverage rate, and the solvent recovery. Environmental issues. For this reason, applicants have many improvement issues in view of the prior art. In order to make cyclobenprine more effective in the extended release dosage form, the effect of eliminating skeletal muscle relaxation is improved, and the preparation method of the dosage form is improved to achieve the reduction. Production costs, increase production efficiency, and reduce the environmental and human hazards of the process.

One aspect of the present invention provides an extended release dosage form composition comprising a selected from the group consisting of Cyclobenzaprine, Dantrolene Sodium, Methocarbamol, and Metaxalone ( Metaxalone), Carisoprodol, Diazepam or its pharmaceutically acceptable salts, solvates and/or esters, as well as extended release interstitials, filling excipients, lubricated forms Excipients such as agents and slipping agents.

The present invention provides a delayed release dosage form of skeletal muscle relaxation, wherein the skeletal muscle relaxant is selected from the group consisting of Cyclobenzaprine, Dantrolene Sodium, Methocarbamol, and metaxalone. (Metaxalone), Carisoprodol, Diazepam or a pharmaceutically acceptable salt, solvate and/or ester thereof, particularly selected as cyclobenzine or its medicinal Acceptable salts, solvates and/or esters. The dosage form is compared with the US Pharmacopoeia solubility test method, using a rotation speed of 50 rpm per minute, using 900 mL of 0.1 N HCl or a suitable dissolution medium as a dissolving solution, and maintaining the water bath temperature at 37 ° C as a dissolution condition for the dissolution test. The effect of delayed release can be achieved: within 30 hours, about 30%-45% of the total active ingredient (drug) is released. Approximately 45%-70% of the total active ingredient was released within 4 hours; and over 65% of the total active ingredient was released within 8 hours.

Another aspect of the present invention provides a skeletal muscle relaxation extended release dosage form that does not contain an extended release coating (membrane); the extended release dosage form does not require the addition of any organic acid, mineral acid, and particularly glyceryl behenate.

Another aspect of the present invention provides a simple method for preparing a cyclic benzrine extended release dosage form comprising the steps of: cyclobenpramine or a pharmaceutically acceptable salt, solvate and/or ester thereof And uniformly mixing the extended release matrix, the filling excipient, and the slipping excipient to form a first mixture; uniformly mixing the lubricating excipient with the first mixture to form a second mixture; and directly pressing the second mixture to form a delayed release The dosage form is prepared by adding an organic solvent, an aqueous solvent, distilled water or any organic acid material.

The present invention is an innovative formulation and process, and provides a simple and economical benefit of a cyclic release form of cyclobenzine or a pharmaceutically acceptable salt, solvate and/or ester, and a preparation method thereof, in particular Preparation of a tablet; the in vitro drug release profile exhibited by the extended release dosage form of the invention has an extended release effect of at least 8 to 12 hours.

The first picture shows the total release of different physiologically used dosage forms.

A-Available dosage form B-Usable dosage form C-Optimal dosage form D-Amrix ER

The second figure shows the total amount of release of the tablet 06-09

Figure 3 Total release of tablets 06-09, 16

Figure 4 Total release of tablets 10-13

Figure 5 Total release of tablets 10-13, 16

Figure 6 Lactose and hydroxypropyl methylcellulose content of tablets

Figure 7 Total release of tablets 8, 13, 16

Figure 8 Total release of tablets 12, 27-29

Figure 9 Total release of tablets 03 and 09

Figure 11 Total release of tablets 12, 16 and tablets 18, 21

Figure 11 Total release of tablets 12 and film-coated tablets 14-15

Interstitial polymers suitable for extended release dosage forms, including hydrophilic interstitial (Hydrophilic Matrix) or hydrophobic interstitial (Hydrophobic Matrix). Among them, the hydrophilic interstitial can be selected from non-ionic Soluble Cellulose Ether, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (hydroxylpropylcellulose), hydroxyethyl Cellulose (Hydroxylethylcellulose). A water-soluble natural gum or a polysaccharide compound of natural origin, such as Xanthum gum, Alginate, and Locust Bean gum. And cross-linked high amylose starch, nonionic ethylene oxide-containing homopolymer (Homopolymer), carboxyvinyl (Carbopol), copolyvidone (Kollidone SR), ionic methyl A polymer homopolymer which is swellable in contact with water, such as an acrylate copolymer acrylic resin (Eudragit). Hydrophobic interstitials may be selected from fatty acid-containing esters, natural or synthetic waxes, and insoluble polymers include Ammoniomethacrylate, dispersion polymers of cellulose and Latex, etc. Polymer homopolymer type with no swelling or swelling.

Generally, a method for producing a tablet: a wet granulation method, a dry granulation method, and a direct compression method can be applied to an interstitial tablet. Wet granulation method (Wet Process, Wet Granutaion), usually mixing the main component compound with an excipient such as a filling excipient or a slipping agent, and adding sodium carboxymethyl cellulose (Sodium CMC), sucrose, and crystallites. Cellulose (Microcrystalline Cellulose, Adhesives such as MCC), honey, starch paste, etc., are pressed and pulverized into granules (Granules). Water or organic solvents are required during manufacture and must be heated or otherwise dried. The Dry Process combines a main component compound with various excipients. Although it excludes water or an organic solvent, and a heat source or drying step, it must be pressurized and pulverized into particles. In the direct pressing method, the main component compound is directly mixed with various excipients without passing through a granulation step, and pressurized to prepare a tablet.

If the dosage form of the pharmaceutical product affects its active ingredient, it will affect the clinical efficacy of the product. In order to meet the physical properties of the active ingredient and the tablet, the preparation method and the added excipient are selected, and the effect of rapidly reducing the condition is obtained. The properties of the tablet manufactured by the pressing method, such as appearance, hardness, uniformity, disintegration ability, and appropriate in vitro dissolution, are affected by the preparation method and the addition of the excipient in the production.

The interstitial lozenge produced by the granulation method by adding distilled water is easily crushed when subjected to mechanical stress and rapidly disintegrates in water, resulting in acceleration of drug release. After wet granulation, the manufacturing process must be subjected to a drying step to reduce the moisture content of the interstitial lozenge to obtain a sufficiently stable product. However, the drying step is sufficient to affect the hardness of the tablet and the possibility of brown spots in the tablet. In the case of granulation with an organic solvent such as ethanol, a mechanically strong interstitial lozenge can be obtained, and the drug distribution is relatively uniform. However, the crosslinked structure of ethanol in the granulation process, although providing strong mechanical properties, results in impaired swelling properties of such tablets.

The preparation method of the extended release dosage form of the invention comprises the method of uniformly mixing the active main component with the necessary excipient, and then adopting a method of directly pressing into a dosage form. The above method may be carried out according to the pharmaceutically-known or customary tablet method, according to the physical characteristics of the main component and the excipient, and may be selected by sieving or batching, sieving, or evenly, to achieve a uniform mixing target. Screening and mixing in a fixed form.

In the dosage form granulation process, organic solvents are usually added to assist the mixing of the drug ingredients. However, the China National Food and Drug Administration reveals the guiding principle number [H]GPH7-1. The technical guidelines for the study of residual solvents in chemical drugs, from the theory mentioned above, the preparation of the drug and the participation in the excipients, if the process uses some organic solvents, may present residues, the residual solvent conditions directly affect the quality of the preparation and many organic solvents There are some dangers that cannot be ignored in the environment and the human body.

The filling excipient comprises lactose, spray-dried lactose, mannitol or a mixture thereof, and the glidant comprises cerium oxide, one of gelled cerium oxide or a mixture thereof, and the lubricating agent is selected from hard fat. Magnesium; the extended release matrix comprises sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), crosslinked hydroxypropylcellulose, hydroxyisopropylcellulose, One of hydroxybutyl cellulose, hydroxyphenyl cellulose, hydroxyethyl cellulose, and hydroxypentyl cellulose or a mixture thereof. The different forms of lactose available for direct compression, if not otherwise, are suitable for the extended release dosage form of the cyclic benzepine of the present invention. Among them, spray-dried lactose has good flow and compression properties, and its stability is still high even under wet conditions. As a sliding excipient, cerium oxide has a large number of pharmaceutically acceptable cerium oxide products, gelled cerium oxide (Aerosil 200) or cerium oxide, and is not suitable for the extension of the cyclic benzepine of the present invention unless otherwise specified. Release dosage form. Hydroxypropyl methylcellulose (HPMC), according to different viscosity, different models, including 90SH-4000SR (HPMC 4000), 90SH-15000SR (HPMC 15000), etc., if not special cases apply to the cyclic benzyl of the present invention Prin's extended release dosage form.

Comparing the commercially available product with the cyclic benzidine extended release dosage form disclosed in the present invention, a clinically suitable dosage form containing cyclobenzine as a main component can be obtained. The drug release profile is shown in the first figure as the total release profile of different physiologically available dosage forms, wherein the clinically suitable physiologically stimulable dosage form, the usable dosage form, the non-distributive dosage form, and the current commercial product of Cyclobenprine, various The dosage form was tested at a dissolution rate of 0.1 mL of a 0.1 N HCl solvent at a frequency of 50 rpm using a machine VK7010 and a bath temperature maintained at 37 ° C.

The clinically appropriate drug release profile should not deviate from the city from 2 to 16 hours. It is preferred that the total active ingredient of the product be released in a proportion of about 10% or more.

According to the total release of cyclobenzine as a main component in physiologically available dosage forms, as shown in Table 1, the classification that can be distinguished from the clinically physiologically effective dosage forms is that the total release amount in 4 hours has been released to a maximum of 51.0-58.2%. A dosage form that is considered to be usable or ideally released. In the case of the dissolution test, the total amount of release after 8 hours was close to half or less of 48.3-62.9%, and it was judged to be a poor release formulation of extended release.

The extended release ingot prepared by the present invention is shown in Table 2. According to the prescription requirement, the proper amount of lactose, cerium oxide, hydroxypropyl methylcellulose, magnesium stearate and the like are used as excipients. The dosage form may be sieved one by one according to requirements, or may be mixed by batching, and the tablet may be prepared by pressurization. Typically, the extended release ingot of cyclobenzine is 220-250 filaments per ingot. The cyclic benzidine content is from 6% (w/w) to 14% (w/w) of the total weight of the tablet. The lactose content is 5% (w/w) to 80% (w/w), or 9% (w/w) to 70% (w/w), or 35% (w/w) of the tablet. Up to 65% (w/w). The hydroxypropyl methylcellulose content is from 15% (w/w) to 85% (w/w), or from 20% (w/w) to 81% (w/w), or 25% of the total weight of the tablet. %(w/w) to 55% (w/w). The cerium oxide content is from about 0.5% to about 2%, or about 0.9%, based on the total weight of the tablet, and the magnesium stearate is from about 0.5% to about 3.5%, or about 1.3%, based on the total weight of the tablet.

The preparation method of the cyclic benazine extended release ingot of the invention comprises the following steps (a.) according to the prescription: cyclobenpramine hydrochloride, spray-dried lactose, hydroxypropylmethylcellulose, gelled cerium oxide according to the prescription 200, after mixing the materials uniformly, mixing into a first mixture through a sieve; (b.) passing the finely called magnesium stearate through a sieve, mixing the first mixture with (a.), and passing through the sieve Forming a second mixture; (c.) directly forming the second mixture via pressurization.

The ratio of the lactose content of the released ingot to the hydroxypropyl methylcellulose content affects the release of the tablet. As shown in Table 3, the formula of the tablet 06-09, the total amount of the lactose content and the hydroxypropyl methylcellulose content in each formula are about 90% of the total weight ratio of the tablet, and the hydroxypropyl group The content of methylcellulose is reduced from 81.81% to 50.00%, and the lactose content is increased from 9.09% to 40.91% of the total weight of the tablet, as shown in Table 4 and Figure 2. The content of lactose in the formula and the reduction of the content of hydroxypropyl methylcellulose can make the delayed release effect of the tablet exhibit the expected delayed release effect.

The formulation of the tablet 06-09 is in the order of increasing the ratio of lactose to the whole weight of the tablet from 9.09% to 40.91%, while the formulation of the tablet 5 is 56.82%, and the hydroxypropylmethyl fiber is relatively The content of the prime is less than either of the formulas of the tablets 06-09. As shown in the third figure, the tablet 06-09 was compared with the delayed release effect of the tablet 16, and the tablet 16 exhibited an unexpected delayed release phenomenon.

As shown in Table 5, the composition of the tablets 10-13 and the tablet 16 has a total amount of lactose content and hydroxypropyl methylcellulose content of 90.41% of the total weight of the tablet, and the lactose content of the tablet 10 The content of hydroxypropyl methylcellulose is similar to that of hydroxypropyl methylcellulose. After increasing the content of lactose and lowering the content of hydroxypropyl methylcellulose, the hydroxypropyl methylcellulose content of tablet 13 accounts for 29.03% of the lactose content. . Lozenges 10-13 as shown in Tables 7 and 4, from 2 hours to 16 hours When the total amount is released, the delayed release of the tablet can be prolonged, which is quite similar to the formulation of the tablet 06-09.

The formulation of the tablets 10-13 and the tablet 16 has a lactose content similar to that of the hydroxypropyl methylcellulose content, while increasing the lactose content and lowering the content of hydroxypropyl methylcellulose. As shown in Table 6, the two-component ratio tablet 06 is 33.33%, the tablet 07 is 66.67%, the tablet 08 is 11.11%, the tablet 09 is 81.82%, and the tablet 11 is 122.22%. 16 is 166.68%, tablet 12 is 207.69%, and tablet 13 is 344.44%. Compared with the delayed release effect between the tablet 06-09 and the tablet 16 shown in the third figure, as shown in Tables 7 and 5, the tablet 13 in the delayed release effect of the tablet 10-13 and the tablet 16 A better delayed release phenomenon is exhibited.

As shown in the sixth figure, the composition of the tablets 8, 13 and the tablet 16 is such that the lactose content of each tablet is close to the total value of the hydroxypropyl methylcellulose content, which is about 90% of the total weight of the tablet. The content of lactose in the tablets 8, 16 and the tablet 13 increased sequentially, and the content of the relative hydroxypropyl methylcellulose was sequentially lowered. Then, as shown in the seventh figure, the ratio of the lactose content to the hydroxypropyl methylcellulose content is compared with the effect of the delayed release between the tablets 8, 13 and the tablet 16, and the release effect of the tablet is affected. The delayed release effect is more prolonged than expected for tablet 8 and tablet 13.

The formulation of the tablets 27-29 is based on the formulation of the tablet 12 and different delayed-release celluloses are used to evaluate whether the difference in cellulose affects the release effect of the tablet. As shown in Table 8, the tablet 27 was made of low-substituted hydroxypropyl cellulose (L-HPC), the tablet 28 was made of ethyl cellulose (Ethyl cellulose), and the tablet 29 was made of hydroxypropyl methylcellulose (HPMC) 15000. Each formulation was directly pressurized under the above preparation method to prepare a tablet.

The tablets 27-29, as shown in Tables 9 and 8 above, released the total amount from 2 hours to 16 hours, in which the delayed release effect of the tablet 29 was similar to that of the tablet 12, and the formulation of the tablet 29 was used. Hydroxypropyl methylcellulose (HPMC) 15000 and tablet 12 are similar in composition of hydroxypropylmethylcellulose 90SH-4000SR.

As shown in Table 10, the composition of the tablet 01-03, the pressed tablet exhibits viscosity and is insufficient in hardness and easily collapses, and thus the tablet is not suitable. The content of glycerol behenate in the total weight of the tablet is increased from 28% to more than 31%, and the formulation of the tablet 02 is glycerol behenate and hydroxypropyl methylcellulose. the same. In the other direction of adjustment, choose low-substituted hydroxypropyl cellulose which will account for 28% of the total weight of the tablet, use 40% hydroxypropyl methylcellulose, and even adjust the total weight of lactose from 34.0%. Up to 17.78%, the pressed tablets still have capping, which is not applicable. Although the tablet 03 and the tablet 09, as shown in the ninth figure, released the total amount at 2 hours to 16 hours, the appearance was quite similar.

(Note) Synthetic aluminum silicate is Aluminum Silicate Synthetic

As shown in Table 11, the formulations of tablets 17-18 and tablets 21, the lactose content, the citric acid content and the hydroxypropyl methylcellulose content of each tablet add up to the total weight of the tablet, and the tablet 17 For the case of 91.48%, the tablet 18 and the tablet 21 were 90.92% and 90.91%, and this composition showed a significant difference from the formulation group of the tablet 01-03. In the formulation of tablet 01, the glycerol behenate content and the hydroxypropyl methylcellulose content plus the total value accounted for 80% of the total weight of the tablet, the tablet 03 was 88.89%, and the lactose-free ingot was added. Agent 02 represents 56% of the total weight of the tablet.

The lactose content of the tablet 16 formulation was 56.82% of the total weight of the tablet, the hydroxypropyl methylcellulose content was 34.09% of the total weight of the tablet, and the lactose content of the tablet 12 formulation was 61.36% of the total weight of the tablet. The hydroxypropyl methylcellulose content was 29.55% based on the total weight of the tablet. Since the lactose content of the tablet 18 formulation is 56.82% of the total weight of the tablet, the hydroxypropyl methylcellulose content is 29.55% of the total weight of the tablet, and the lactose content of the tablet 21 formulation is 59.09% of the total weight of the tablet. The hydroxypropyl methylcellulose content is 29.55% of the total weight of the tablet.

As shown in the tenth figure, the tablet 12 and the tablet 16 are compared with the total amount of the tablets 18 and 21, and exhibit a similar release phenomenon. However, when the color of the finished product is observed, when the citric acid is added to the formulation, the process of directly mixing the main component with various excipients to form a tablet is sufficient to cause the appearance of the finished product to be suddenly unstable. .

(Note) The tablet 21 was mixed with 20 ml of 95% alchol and then pressed to prepare a tablet.

The above-mentioned tablet preparation method may be further coated with a sugar coating or a film coating as necessary to form a sugar coating or a film coating tablet. Generally, the tablet is firstly pressed into a tablet according to the above formula, and then the prepared sugar coating or film coating solution is placed in a sugar coating or a film coating pan according to the preparation method of the sugar coating or the film coating to form a sugar coating or a film coating. For example, the tablet 12 is compressed according to the formulation, placed in a film coat pan, and the film coat I solution is added to form a film coat tablet 14. Further, the tablet 12 is compressed according to the formulation, placed in a film coat pan, and a film coat II solution is added to form a film-coated tablet 15.

The main difference between the composition of the film I solution and the film coat II solution is that the former dissolves hydroxypropyl methylcellulose (HPMC 606) with alcohol, and the latter dissolves only the entire film coat composition in distilled water. In addition, the film coating I solution composition contains hydroxypropylmethylcellulose phthalate (HP-55), and the film coat II solution composition does not contain this component. The main differences in other compositions are shown in Table 12. The content of Titanium Dioxide and Iron Sesquioxide Yellow in the film II solution was slightly lower.

The film I solution was prepared by dissolving 3.5 g of hydroxypropyl methylcellulose (HPMC 606) in 104 ml of 95% alcohol and 1.5 g of polyethylene glycol (PEG 6000) in 26 g. ML of distilled water, 9 grams of hydroxypropyl methylcellulose phthalate (HPMCP, HP-55) dissolved in 50 ml of distilled water, adding 0.77 grams Titanium Dioxide, 0.2 g of Iron Sesquioxide Yellow.

The film II solution was prepared by dissolving 3.5 g of hydroxypropyl methylcellulose (HPMC606), 1.5 g of polyethylene glycol (PEG 6000) in 50 ml of distilled water, and adding 0.38 g of Titanium Dioxide. , 0.1 g of yellow iron oxide (Iron Sesquioxide Yellow).

The tablet 12 is compressed according to the formulation, and the film coating I solution is added to form the film coating tablet 14, or the film coating II solution is changed, and the tablet 12 is formed into the film coating tablet 15. Adding a film I solution as shown in Table 12 and Figure 11, or a film coat II solution, in a 0.1 N HCl solvent 900 mL, at a 50 rpm oscillation frequency in a partial acid dissolution mode, the prepared tablet 12, film ingot The total amount of release of the agent 14 and the film-coated tablet 15, the three tablets, is limited.

The term "about" and "a" or "an" or "an" or "an" range. As used herein, "about" will be known and understood by those skilled in the art, and it will vary to some extent in the context of its use. If the person skilled in the art is not clear about the use of the term in the context of using the term, then "About" will mean ±10% of the maximum value.

The terms "drug", "active ingredient", "drug main ingredient", and "active main ingredient" mean that the compound, antibody, protein and other ingredients have medicinal physiological activity, and the terms can be used interchangeably. The meanings are the same.

The terms "extended release", "extended release", and "sustained release" are used interchangeably, and their meanings and connotations are the same. The terms "free solvent or solvent mixture" and "free solvent" mean that the step of preparing the dosage form does not use dry granulation with the addition of an organic solvent or a solvent mixture. The direct compression method is adopted, and an organic solvent, an aqueous solvent, and distilled water are not added to dissolve the main component or the excipient.

The term "excipient" or "pharmaceutically acceptable carrier or excipient" and "bioavailable carrier or excipient", any suitable compound used in the preparation of the dosage form, including known excipients Such as solvents, dispersants, coatings, antibiotics, antifungals and preservatives or delayed water absorbing agents. Usually, the carrier or excipient itself does not have a therapeutic effect. The present invention discloses a formulation in which a derivative is combined with a pharmaceutically acceptable carrier or excipient, administered to an animal or human, without causing an unintended reaction, allergy or other undue influence. Thus, the formulations disclosed in the present invention in combination with pharmaceutically acceptable carriers or excipients and derivatives are suitable for use in human clinical applications.

In summary, all of the technical and scientific terms described in this specification, unless otherwise defined, are intended to be within the ordinary skill of the art. The present invention is exemplified by the following examples, but the present invention is not limited by the following examples. The drugs and materials used in the present invention are all commercially available and easy to obtain. The following are only examples of available pipes.

The invention is an innovative invention, which comprises cyclobenzaprine or a pharmaceutically acceptable salt, solvate and/or ester thereof, and a delayed release interstitial, a filling excipient, a slipping excipient, Lubricate excipients such as excipients. The preparation process is to uniformly mix the materials, no It is necessary to add an organic solvent, an aqueous solvent, distilled water or any organic acid material, and directly pressurize to prepare an extended release dosage form. The in vitro dissolution test was used to confirm that the extended release tablets have clinically available total available release, which has deep industrial value and is submitted in accordance with the law. In addition, the present invention may be modified by those skilled in the art without departing from the scope of the appended claims.

The present invention will be fully understood by the following examples, which can be accomplished by those skilled in the art. However, the implementation of the present invention is not limited by the following embodiments, and those skilled in the art can still rely on the present invention. Other embodiments are intended to be included within the scope of the invention.

Example:

Example 1 Cyclopenzaprine extended release dosage form

The preparation method comprises the following steps: (a.) separately according to the prescription, cyclobenzine, lactose, hydroxypropylmethylcellulose 90SH-4000SR, gelled cerium oxide 200, and the materials are uniformly mixed, passed through a sieve, and mixed. (b.) passing magnesium stearate through a sieve, mixing the material with (a.), and then mixing through a sieve; (c.) directly forming the tablet by pressurization. It is not necessary to additionally add an organic solvent, an aqueous solvent or distilled water in the above preparation process. This formulation is in a 0.1 N HCl solvent with a dissolution rate similar to that of the commercial Amrix ER Capsules.

Example 2 Preparation for clinical use of tablet 06-09

Formulation of Lozenge 06-09

The preparation method was carried out by directly pressing the tablet according to Example 1.

Example 3 Preparation of clinical use of tablet 10-13

Formulation of tablet 10-13

The preparation method was carried out by directly pressing the tablet according to Example 1.

Example 4 Preparation of Clinical Application of Lozenges 16 and Lozenges 29

Formulation of tablet 16 and tablet 29

The preparation method was carried out by directly pressing the tablet according to Example 1.

Example 5 Non-available dosage form

Preparation method: (a.) cyclobenzine, lactose, citric acid, hydroxypropyl methylcellulose 90SH-4000SR, gelled cerium oxide 200 are uniformly mixed, passed through a sieve, mixed; (b.) Magnesium stearate is passed through a screen, mixed with a., and passed through a screen; (c.) is made into a tablet by pressurization.

Example 6 Non-available dosage form

Preparation method: (a.) cyclobenzine, lactose, glyceryl behenate, hydroxypropyl methylcellulose 90SH-4000SR, gelled cerium oxide 200 are uniformly mixed, passed through a sieve, and mixed; b.) Magnesium stearate is passed through a sieve, mixed with (a.), and passed through a sieve; (c.) directly pressurized to form a tablet. After the final preparation of the tablet into a tablet, the preparation method was found to have insufficient hardness or even an adhesive state, and thus it was in an unattainable state.

Other embodiments

A process for preparing a delayed release dosage form comprising the following steps of adding an organic solvent, an aqueous solvent, distilled water or a solvent mixture: (a) cyclobenzaprine or a pharmaceutically acceptable salt thereof a solvate, a solvate and/or an ester; and a delayed release interstitial, a filling excipient, a slip-forming agent uniformly mixed to form a first mixture; (b) uniformly mixing magnesium stearate with the first mixture to form a second mixture (c) pressurizing the second mixture to form a dosage form.

2. The preparation method of embodiment 1, wherein the filling excipient is one of lactose, spray-dried lactose, and mannitol; and the delayed release interstitial is one of hydroxypropyl methylcellulose (HPMC); wherein the excipient is filled The total weight of the dosage form is 5% (w/w) to 80% (w/w), and the cerium oxide accounts for 0.5% (w/w) to 2% (w/w) of the total weight of the dosage form, and magnesium stearate accounts for The total weight of the dosage form is from 0.5% (w/w) to 3.5% (w/w), and the extended release interstitial comprises from 15% (w/w) to 85% (w/w) of the total weight of the dosage form.

3. A method for preparing an interstitial dosage form without adding an organic solvent, the method prepared by the method exhibiting skeletal muscle relaxation activity, the step comprising: (a.) cyclobenzaprine or a pharmaceutically acceptable salt thereof a solvate, a solvate and/or an ester; and a delayed release interstitial, a filling excipient, a slipping excipient uniformly mixed to form a first mixture; (b.) uniformly mixing magnesium stearate with the first mixture to form a second a mixture; (c.) pressurizing the second mixture to form a delayed release dosage form; without adding an organic solvent based organic solvent, an aqueous solvent, distilled water or a solvent mixture.

4. The preparation method according to embodiment 3, wherein the filling excipient is one of lactose, spray-dried lactose, and mannitol; the sliding excipient is one of cerium oxide and gelatinized cerium; the extended-release interstitial is carboxy Sodium methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), crosslinked hydroxypropylcellulose, hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenyl One of cellulose, hydroxyethyl cellulose and hydroxypentyl cellulose; the filling excipient accounts for 9% (w/w) to 70% (w/w) of the total weight of the dosage form, and the slipping excipient accounts for the total amount of the dosage form. The weight is 0.5% (w/w) to 2% (w/w), magnesium stearate accounts for 0.5% (w/w) to 3.5% (w/w) of the total weight of the dosage form, and the extended release matrix accounts for the total dosage of the dosage form. The weight is 20% (w/w) to 82% (w/w).

5. A pharmaceutical composition for extended release dosage form comprising: a main active ingredient being cyclobenzaprine or a pharmaceutically acceptable salt, solvate and/or ester thereof; and a delayed release interstitial, The excipient, cerium oxide, magnesium stearate may be filled, and if necessary, a pharmaceutically acceptable excipient may be added.

6. The pharmaceutical composition according to embodiment 5, wherein the filling excipient is one of lactose, spray-dried lactose, and mannitol; the delayed release interstitial is sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl One of cellulose (HPMC), crosslinked hydroxypropylcellulose, hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose, and hydroxypentylcellulose Wherein the filling excipient accounts for 9% (w/w) to 70% (w/w) of the total weight of the dosage form, and the cerium oxide comprises 0.5% (w/w) to 2% (w/w) of the total weight of the dosage form. , magnesium stearate accounts for 0.5% (w/w) to 3.5% (w/w) of the total weight of the dosage form, and the extended release interstitial accounts for 20% (w/w) to 82% (w/w) of the total weight of the dosage form. .

7. A method of preparing an extended release dosage form, the method comprising the steps of: (a) cyclobenzaprine or a pharmaceutically acceptable salt, solvate and/or ester thereof; and extended release The mass, the filling excipient, and the slipping excipient are uniformly mixed to form a first mixture; (b) the magnesium stearate is uniformly mixed with the first mixture to form a second mixture; and (c) the second mixture is pressurized to form a dosage form.

8. The method of embodiment 7, the filling excipient is lactose, spray dried milk One of sugar and mannitol; the slipping excipient is one of cerium oxide and gelled cerium oxide; the delayed release interstitial is sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose ( HPMC), one of crosslinked hydroxypropylcellulose, hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose, and hydroxypentylcellulose.

9. The method of embodiment 7, wherein the filling excipient comprises from 5% (w/w) to 80% (w/w) of the total weight of the dosage form, and the cerium oxide comprises 0.5% (w/w) of the total weight of the dosage form. To 2% (w/w), magnesium stearate accounts for 0.5% (w/w) to 3.5% (w/w) of the total weight of the dosage form, and the extended release matrix accounts for 15% (w/w) of the total weight of the dosage form. Up to 85% (w/w).

10. A composition for the preparation of an extended release dosage form comprising: the main active ingredient is cyclobenzaprine or a pharmaceutically acceptable salt, solvate and/or ester thereof And a delayed release interstitial, a filling excipient, cerium oxide, magnesium stearate, and if necessary, a pharmaceutically acceptable excipient; the composition exhibits skeletal muscle relaxation activity.

11. The pharmaceutical composition according to embodiment 10, wherein the filling excipient is one of lactose, spray-dried lactose, and mannitol; the delayed release interstitial is sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl One of cellulose (HPMC), crosslinked hydroxypropylcellulose, hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose, and hydroxypentylcellulose; The excipient accounts for 9% (w/w) to 70% (w/w) of the total weight of the dosage form, and the cerium oxide accounts for 0.5% (w/w) to 2% (w/w) of the total weight of the dosage form, and the hard fat The magnesium acid comprises from 0.5% (w/w) to 3.5% (w/w) of the total weight of the dosage form, and the extended release interstitial comprises from 20% (w/w) to 82% (w/w) of the total weight of the dosage form.

references

As defined in the specification

Claims (10)

A method of preparing an extended release dosage form, the method comprising the steps of: a. treating cyclobenzaprine or a pharmaceutically acceptable salt, solvate and/or ester thereof; and filling the excipient, sliding The excipient, the extended release matrix are uniformly mixed to form a first mixture; b. the lubricating excipient is uniformly mixed with the first mixture to form a second mixture; and the second mixture is pressed into a dosage form; wherein the filling excipient is lactose , spray-dried lactose, mannitol or a mixture thereof; the sliding excipient is cerium oxide, one of gelled cerium oxide or a mixture thereof; the lubricating excipient is magnesium stearate; the delayed release interstitial is hydroxypropyl Methyl cellulose (HPMC). The method of claim 1, wherein the filling excipient accounts for 5% (w/w) to 80% (w/w) of the total weight of the dosage form, and the slipping excipient accounts for 0.5% of the total weight of the dosage form (w/w) ) to 2% (w/w), the lubricating excipients accounted for 0.5% (w/w) to 3.5% (w/w) of the total weight of the dosage form, and the extended release interstitial accounted for 20.45% of the total weight of the dosage form (w/w) ) to 45.45% (w/w). The method of claim 1 or 2, wherein the drug release profile of the extended release dosage form is 900 mL in 0.1 N HCl solvent, using a machine VK7010 at a 50 rpm oscillation frequency, and the water bath temperature is maintained at 37 ° C. Within 30 hours, about 30%-45% of the total active ingredient (drug) is released; within 4 hours, about 45%-70% of the total active ingredient is released; and within 8 hours, about 65% of the total active ingredient released. The method of claim 3, wherein the filling excipient is spray dried lactose. The method of claim 4, wherein the method further comprises coating the dosage form with a sugar coating or a film coating, if necessary. A pharmaceutical composition, which is an extended release tablet, the pharmaceutical composition comprising: Cyclobenprazole, the total weight of the tablet is 6% (w/w) to 14% (w/w); one of lactose, spray-dried lactose or a mixture thereof, the content of which is 35% of the total weight of the tablet (w/ w) to 65% (w/w); hydroxypropyl methylcellulose in an amount of 20.45% (w/w) to 45.45% (w/w) based on the total weight of the tablet; cerium oxide, gelled cerium oxide One of them or a mixture thereof is present in an amount of from about 0.5% to about 2% by weight based on the total weight of the tablet; magnesium stearate is present in an amount of from about 0.5% to about 3.5% by weight based on the total weight of the tablet. The pharmaceutical composition of claim 6, wherein the hydroxypropyl methylcellulose is present in an amount of 20.45% (w/w) to 40.91% (w/w) based on the total weight of the tablet; cerium oxide, gelled dioxide The mash or a mixture thereof is present in an amount of about 0.9% by weight based on the total weight of the tablet; magnesium stearate is present in an amount of about 1.3% by weight based on the total weight of the tablet. The pharmaceutical composition according to claim 6 or 7, wherein the drug release profile of the extended release of the pharmaceutical composition is 900 mL in 0.1 N HCl solvent, using a machine VK7010 at a frequency of 50 rpm, and the bath temperature is maintained at 37 ° C. Under the test, about 30%-45% of the total active ingredient (drug) was released within 2 hours; about 45%-70% of the total active ingredient was released within 4 hours; and about 65% within 8 hours. The above total active ingredients are released. The pharmaceutical composition of claim 6 or 7, wherein the pharmaceutical composition is further coated with a sugar coating or a film coating as necessary. The pharmaceutical composition of claim 8 which is prepared by the following steps: a. cyclobenzine; one of lactose, spray-dried lactose or a mixture thereof; cerium oxide, gelatinized cerium oxide. One or a mixture thereof; and hydroxypropyl methylcellulose are uniformly mixed to form a first mixture; b. magnesium stearate is uniformly mixed with the first mixture to form a second mixture; and the second mixture is pressurized to form a dosage form.