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    • 专利摘要:
    The present invention relates to pharmaceutical compositions for oral administration. The compositions are aqueous premixed suspensions of methylprednisolone and / or homogeneous aqueous suspensions of methylprednisolone. The pharmaceutical compositions include either about 2 mg / ml to about 4 mg / ml of methylprednisolone, or alternatively about 3 mg / ml to about 4 mg / ml of methylprednisolone. The pharmaceutical compositions are exceptionally stable on storage and have a pleasant taste.
    公开号:BE1025934B1
    申请号:E20195008
    申请日:2019-01-09
    公开日:2020-05-05
    发明作者:Thomas Gerner Jacobsen；Ioannis Psarrakis；Konstantinos Lioumis
    申请人:Hyloris Dev Sa；
    IPC主号:
    专利说明:

    SUSPENSI ON PHARMACEUTI QUE DE METHYLPREDNÎ SOLONE
    REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the advantage of the provisional American patent application No. 62 / 616,556, filed on Friday, January 12, 2018, the description of which is incorporated herein by reference in its entirety.
    TECHNICAL FIELD The present invention relates to a pharmaceutical suspension of methylprednisolone for oral administration which has acceptable taste characteristics and long-term stability.
    BACKGROUND [0003] Methylprednisolone is a corticosteroid. The chemical name of methylprednisolone is 113,17,21-trihydroxy-6o-methylpregna-1,4-diene3,20-dione and its molecular weight is 374.5. It has the following chemical structure:
    [0004] Methylprednisolone is mainly used as an anti-inflammatory or immunosuppressive agent in the treatment of various diseases, in particular those of hematological, allergic, inflammatory, neoplastic and autoimmune origin. For example, methylprednisolone relieves inflammation (swelling, heat, redness and pain) and is used to treat certain forms of arthritis; skin, blood, kidney, eye, thyroid, and intestinal conditions (for example, colitis); severe allergies; and asthma. Methylprednisolone is also used to treat
    BE2019 / 5008 certain types of cancer. Unfortunately, methylprednisolone has a bitter and very unpleasant taste. It is also practically insoluble in water. [0005] Methylprednisolone acetate and sodium succinate salts are available in the form of injectable compositions. Depo-Medrol® (methylprednisolone acetate suspension for injection, 20 mg / ml, 40 mg / ml and 80 mg / ml) is available for intramuscular, intra-articular, soft tissue or intralesional injection. Depo-Medrol® (sterile aqueous suspension of methylprednisolone acetate, 20 mg / ml and 40 mg / ml) is available for intramuscular and intrasynovial injection in horses and dogs, and intramuscular injection in cats. Solu-Medrol® (methylprednisolone sodium succinate for injection, 40 mg / ml, 125 mg / 2 ml, 500 mg / 4 ml, 500 mg / 8 ml, 1 g / 8 ml, 1 g / 16 ml and 2 g / ml 30.6 ml) is available for intravenous or intramuscular administration.
    Different dosages of oral suspension of methylprednisolone, ranging from 2 mg / ml to 15 mg / ml, are available for animals from Wedgewood Pharmacy on WedgewoodPetRx.com.
    The Allen document, Loyd V. Jr., International Journal of Pharmaceutical Compounding, Vol. 15, No. 4, July / August 2011, describes another oral suspension of methylprednisolone (4 mg / ml). However, the use of this suspension is limited by the lack of sufficient storage stability, i.e. it must be used within 14 days and must be kept in the refrigerator.
    Pharmaceutical suspensions are particularly useful, for example, for pediatric and geriatric patients, because they are easy to swallow. Ready-to-use suspensions promote patient compliance and acceptance by these patient populations. However, they often lack stability during storage. Over time, the suspended drug particles tend to settle and even form a cake, resulting in inadequate or inappropriate dosing.
    There is a need for oral suspensions of methylprednisolone ready to use, stable and with an effectively masked taste.
    SUMMARY The present invention relates to a premixed aqueous suspension for oral administration comprising from about 2 mg / ml to about 4 mg / ml of methylprednisolone. The suspension has a shelf life of at least about 12 months when stored at about 25 ° C and at humidity
    BE2019 / 5008 relative of around 60%.
    The present invention also relates to a premixed aqueous suspension for oral administration. The suspension comprises from about 2 mg / ml to about 4 mg / ml of methylprednisolone; a sweetener in an amount of from about 0.1% by weight to about 2.0% by weight; a preservative in an amount of from about 0.05% by weight to about 1.0% by weight; a suspending agent in an amount of from about 0.05% by weight to about 2.0% by weight; a buffering agent in an amount of from about 0.05% by weight to about 1.0% by weight; a flavoring agent in an amount of from about 0.05% by weight to about 1.0% by weight; and a taste masking agent in an amount from about 0.01% by weight to about 1.0% by weight. The suspension has a shelf life of at least about 12 months when stored at about 25 ° C and at a relative humidity of about 60%.
    In some embodiments, the suspensions described here include about 3 mg / ml to about 4 mg / ml of methylprednisolone. In other embodiments, the suspensions described herein comprise about 3.2 mg / ml of methylprednisolone.
    The invention also relates to a method for treating allergic conditions, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous system diseases, ophthalmic diseases, nephropathies, respiratory diseases, rheumatic diseases, trichinosis with neurological or myocardial involvement, or tuberculous meningitis with subarachnoid or imminent block, comprising the administration of an effective amount of a premixed aqueous suspension of methylprednisolone for oral administration.
    BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the chromatogram provided with methylprednisolone for the conformity of the SCR system referenced in the monograph of the European Pharmacopoeia for methylprednisolone for the identification of impurities.
    BE2019 / 5008
    DETAILED DESCRIPTION The following detailed description is given by way of example and explanatory and the following examples are intended to provide an additional explanation of the pharmaceutical compositions described here. Other characteristics will be readily apparent to those skilled in the art from the following examples which are provided to show the advantageous stability of the pharmaceutical compositions. However, these examples are given for illustration purposes only.
    The present invention relates to pharmaceutical compositions for oral administration. The pharmaceutical compositions are premixed aqueous suspensions of methylprednisolone which are stable on storage. In some embodiments, the composition has a shelf life of at least about 12 months when stored at about 25 ° C and about 60% relative humidity. In some embodiments, the composition has a shelf life of at least about 24 months when stored at about 25 ° C and at a relative humidity of about 60%. In other embodiments, the composition has a shelf life of at least about 36 months when stored at about 25 ° C and at a relative humidity of about 60%. As used herein and as generally understood in the art, the term "shelf life" refers to expiration date information submitted to a regulatory body responsible for approving the marketing of the pharmaceutical composition. In the context of shelf life, "at least" compared to a period in months means that the pharmaceutical composition can be labeled with an expiry date representing the last day of the specified period of time, although it can keep stability properties beyond.
    In some embodiments, the composition retains at least about 90% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about six months. In some embodiments, the pharmaceutical composition retains at least about 90% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about 12 months.
    In other embodiments, the composition can retain at least about 95% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about six months. In some embodiments, the composition can retain at least about 95% of the amount of methylprednisolone released after storage at about 25
    BE2019 / 5008 ° C and around 60% relative humidity for about 12 months.
    In some embodiments, the composition can retain about 95% to about 105% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about six months. In some embodiments, the composition can retain 95% to about 105% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about 12 months.
    The present invention also relates to a pharmaceutical composition for oral administration comprising a homogeneous aqueous suspension. In embodiments of the pharmaceutical compositions described herein, the composition is homogeneous after storage at about 25 ° C and about 60% relative humidity for about a year. In some embodiments, the composition is homogeneous after storage at about 25 ° C and about 60% relative humidity for about 24 months.
    The premixed aqueous suspensions and the homogeneous aqueous suspensions described in this specification include about 2 mg / ml to about 4 mg / ml or, alternatively, about 3 mg / ml to about 4 mg / ml of methylprednisolone. For example, premixed aqueous suspensions and homogeneous aqueous suspensions may comprise about 3.2 mg / ml methylprednisolone.
    The pharmaceutical compositions described here can be prepared, stored and administered appropriately. Since the aqueous suspensions are premixed and / or homogeneous and stable during storage, the pharmaceutical compositions described here can be prepared and stored in a ready-to-use dosage form. "Premixed" means that the dosage form is ready for use, that is, it is manufactured and sold in a form that can be administered directly to patients without any preparation step, such as dilution, is not necessary before administration. Children and geriatric patients, among others, who have difficulty swallowing solid oral dosage forms are likely to benefit from the suspensions described in this document, thereby improving patient compliance and, therefore, treatment results.
    The pharmaceutical compositions described here may include one or more of: a sweetener, a preservative, a suspending agent, a buffering agent, a flavoring agent and a taste masking agent.
    The premixed aqueous suspension and the homogeneous aqueous suspension may further comprise one or more of the following: a
    BE2019 / 5008 sweetener in an amount from about 0.1% by weight to about 2.0% by weight; a preservative in an amount of from about 0.05% by weight to about 1.0% by weight; a suspending agent in an amount of from about 0.05% by weight to about 2.0% by weight; a buffering agent in an amount of from about 0.05% by weight to about 1.0% by weight; a flavoring agent in an amount of from about 0.05% by weight to about 1.0% by weight; and a taste masking agent in an amount from about 0.01% by weight to about 1.0% by weight. As used herein, the term "% by weight" refers to a weight / weight percentage.
    The term "sweetener", as used herein, refers to both caloric and non-caloric sweeteners. Among the sweeteners, mention will be made of acesulfame, alitame, arabinose, aspartame, cellobiose, cyclamate, dextrin, fructose, galactose, glucose, isomalt, lactose, maltodextrin, maltose, mannitol, mannose, monellin, monoammonium glycyrrhizinate, neohesperidin, neotame, oxylose, ribose, saccharin, sorbose, steviol glycoside, sucralose, sucrose, sugar, pharmaceutically acceptable salts thereof, and combinations thereof. The term "steviol glycoside", as used herein, denotes a natural sweetener derived from the leaves of the stevia plant and includes stevioside, steviolbioside, rubusoside, dulcoside A, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E and rebaudioside F. In certain embodiments, the sweetener is selected from sucralose, saccharin sodium and a combination thereof. In some embodiments, the sweetener is a combination of sucralose and sodium saccharin.
    The term "preservative", as used herein, denotes any agent which is included in the suspension to prevent microbial contamination (for example, yeast, mold, bacteria, etc.). Exemplary preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben and their pharmaceutically acceptable salts, cetyltrimethylammonium bromide, chlorhexidine, chlorobutanol, chlorocresol, l alcohol, ethylenediaminetetraacetic acid, ethylparaben and their pharmaceutically acceptable salts, imidurea, methylparaben and their pharmaceutically acceptable salts, phenol, phenylmurcuric salts, pharmaceutically acceptable, potassium sorbate, propylene glycol, propylparaben and their pharmaceutically acceptable salts, sodium benzoate, sodium citrate, sodium propionate, sorbic acid, thimerosol and combinations thereof. In some embodiments, the preservative is the
    BE2019 / 5008 methylparaben sodium.
    The term "suspending agent", as used herein, denotes any agent which helps maintain the methylprednisolone particles in suspension. Exemplary suspending agents include acacia, alginic acid, bentonite, a carbomer, calcium carboxymethylcellulose, carrageenan, colloidal silicon dioxide, crospovidone, dextrin, sublimed silica, gelatin, gum gum guar, hydroxyethylcellulose, hydroxyethylpropylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, methylcellulose, magnesium aluminometasilicate, maltodextrin, microcrystalline cellulose, polydextrose, polyvinyl alcohol, povidone, propylene glycol alginate, propylene glycol alginate sodium, sodium carboxymethylcellulose, starch, tragacanth, xanthan gum, and combinations thereof. In some embodiments, the preservative is xanthan gum.
    The term "buffering agent", as used herein, denotes any agent or combination of agents which resists changes in pH by the action of its acid-base conjugate components. Examples of buffering agents include acetic acid, acetate (e.g. sodium acetate), calcium carbonate, citric acid, disodium hydrogen phosphate, lactic acid, magnesium hydroxide, sodium citrate, phosphoric acid, potassium citrate, sodium citrate, sodium hydrogencarbonate, sodium hydroxide, sodium phosphate, succinic acid, tartaric acid, and combinations thereof. In certain embodiments, the buffering agent is selected from citric acid, sodium citrate and a combination thereof. In some embodiments, the buffering agent is a combination of citric acid and sodium citrate.
    The term "flavoring agent", as used herein, denotes an agent used to induce a feeling of flavor in humans during ingestion and includes natural and synthetic flavoring agents. Examples of flavoring agents include a banana flavoring agent, blackcurrant flavoring agent, caramel flavoring agent, cherry flavoring agent, chocolate flavoring agent, cream flavoring agent, flavoring flavoring agent grenadine, a tutti frutti flavoring agent, a grape flavoring agent, a raspberry flavoring agent, a strawberry flavoring agent, a peppermint flavoring agent, and combinations thereof. In some embodiments, the flavoring agent includes peppermint. In some embodiments, the flavoring agent is a peppermint flavoring agent. In some embodiments, the flavoring agent is an agent
    BE2019 / 5008 flavoring with tutti frutti.
    The term "taste masking agent", as used herein, denotes any agent or combination which potentiates, modifies or improves the palatability of methylprednisolone, which is intrinsically bitter for the human palate. Flavoring agents and sweeteners can act as taste masking agents.
    Alcohols are taste masking agents given by way of example. Other examples of taste masking agents include cyclodextrins, maltodextrin, amino acids, gelatin, gelatinized starch, liposomes, lecithin, lecithin-like substances, their salts and combinations thereof. A "lecithin" is generally a phosphatide present in the egg yolk. As used herein, the term "lecithin-like substances" means phosphatides isolated from animals and plants other than the phosphatide lecithin which is found in egg yolk. For example, "lecithin-like substances" include phosphatides isolated from soy, liver, muscles, kidneys, brain, nerves, blood, etc. As used herein, with reference to flavoring agents, the example salts are the alkali metal bicarbonates such as sodium bicarbonate or monoammonium glycyrrhizinate. In some embodiments, the taste-making agent is a combination of monoammonium glycyrrhizinate, sucralose and maltodextrin. Suitable flavor masking agents are commercially available, for example, SC202039 masking flavor powder available from International Flavors and Fragrance's Inc., Magnasweet® 110, Magnasweet® 110F, Magnasweet® 110 2X, and the Magnasweet® 110 3X.
    In the context of the present, an aqueous suspension is "homogeneous" when each individual dose of the aqueous suspension represents between 85% and 115% of the average dose when the homogeneity is tested, as indicated in the British Pharmacopoeia (2008 ), which is incorporated here for reference in its entirety:
    Homogeneity of the suspension
    Allow an adequate volume of examined oral suspension to settle for 24 hours without being disturbed. Shake the container for 30 seconds and accurately withdraw a dose (usually 5 to 10 ml) to a depth of 1 cm below the
    BE2019 / 5008 meniscus. Shake the container again for 10 seconds and withdraw another dose. Repeat this procedure until 10 doses of the suspension have been withdrawn. Dose the 10 doses individually according to the method indicated in the individual monograph.
    The preparation conforms to the test if each individual dose represents between 85% and 115% of the average dose. The preparation does not comply with the test if more than one individual dose is outside these limits or if an individual dose is outside the limits of 75% to 125% of the average content.
    In some embodiments, methylprednisolone is micronized. As used herein, the term "micronized" refers to methylprednisolone in the form of a fine powder having particles the diameter of which is on the order of a few microns. In some embodiments, the diameter of at least 90% of the micronized methylprednisolone is from about 12 to about 15 microns. In embodiments, about 100% of the micronized methylprednisolone is less than about 30 microns in diameter, about 95% of the micronized methylprednisolone is less than about 15 micrometers in diameter, and about 50% of the micronized methylprednisolone is less than about 5 micrometers. When the micronized methylprednisolone is discussed herein, the particle size is measured by the following method:
    Aircraft: Malvern 2000MU
    Penetration speed in turbulence: 2500 rpm
    Ultrasonic force: 10.00
    Particle refraction index: 1.640
    Result units: volume distribution
    Particle size range: 0.02 ~ 2000 pms
    Obscuration: 10 ~ 20
    Dispersing solution: water
    Preparation of the solution
    1. Prepare a 2% solution of 6-sodium metaphosphate:
    BE2019 / 5008
    Take about 2 g of 6-sodium hexametaphosphate in a 100 ml iodimetric flask and dilute with 100 ml of purified water.
    2. Preparation of the saturated solution:
    Put about 1 to 2 g of sample in a 1000 ml beaker and add 1000 ml of purified water. Shake to obtain the saturated solution. Filter it with a suction flask to obtain a clear solution.
    3. Preparation of the suspension solution:
    Put about 0.5 to 1 g of sample in a beaker and add about 20 ml of purified water to prepare a concentrated suspension solution. Finally, add 1 to 2 drops of 6-sodium metaphosphate solution per burette and distribute them evenly.
    The pH of the suspensions can vary. The pH can be, for example, from about 4.0 to about 6.0. As another example, the pH can be from about 5.0 to about 5.5.
    During storage, methylprednisolone is subject to the formation of impurities. As used herein, the term AL impurities refers to the impurities identified in the European Pharmacopoeia Monograph, Eighth Edition, Volume 2 (2013) on methylprednisolone (p. 2748-2750), which is incorporated herein in its entirety for reference. Consequently, A-L impurities have the following meanings:
    "Impurity A" refers to 17,21-dihydroxy-6o-methylpregna-1,4-diene-
    3,11,20-trione having the following structure:
    BE2019 / 5008 “Impurity B” designates the lip, 17,21,21-tetrahydroxy-6a-methylpregna-1,4,4-diene-3,20-dione having the following structure:
    "Impurity C" denotes lip-hydroxy-6a-methylandrosta-1,4-diene-3,17dione having the following structure:
    “Impurity D” designates the (EZ) -lip, 20-dihydroxy-6a-methylpregna10 l, 4.17 (20) triene-3,21-dione having the following structure:
    "Impurity E" denotes lip-hydroxy-6a-methyl-3-oxoandrosta-1,4-dien-17β-carboxylic acid having the following structure:
    BE2019 / 5008
    "Impurity F" designates 11β, 17.21-trihydroxy-6a-methylpregnn4-ene-3.20-dione having the following structure:
    "Impurity G" denotes 17,21-dihydroxy-6a-methylpregna-1,4,9 (ll) -triene-3,20-dione having the following structure:
    “Impurity H” designates 11β, 17.21-trihydroxy-6ß methylpregna-1,4 diene-3,20-dione having the following structure:
    BE2019 / 5008
    "Impurity I" means a compound having an unknown structure. It is identified as indicated in the monograph for methylprednisolone (p. 2748-2750) of the European Pharmacopoeia, eighth edition, volume 2 (2013), which is incorporated here in its entirety for reference.
    "Impurity J" denotes 113,17-dihydroxy-6o-methyl- acetate
    3,20-dioxopregna-1,4-diene-21-yl (methylprednisolone acetate) having the following structure:
    "Impurity K" means 113,17,21-trihydroxypregna-l, 4-diene-
    3,20-dione (prednisolone) having the following structure:
    "Impurity L" denotes 113,17-dihydroxy-6o-methylpregna-l, 4diene-3,20-dione having the following structure:
    BE2019 / 5008
    The impurities are identified as indicated in the monograph relating to methylprednisolone (p. 2748-2750) of the European Pharmacopoeia, eighth edition, volume 2 (2013). With regard to the identification of impurities, this monograph specifically describes:
    Related substances. Liquid chromatograph (2.2.29).
    Mixture of solvents; phosphoric acid R, acetonitrile R, water R (0.1: 50: 50 V7V7V) Test solution. Dissolve 30.0 mg of the substance to be examined in the solvent mixture and make up to 50.0 ml with the solvent mixture.
    Control solution (a). Dissolve 6 mg of methylprednisolone for compliance with the SCR system (containing impurities A, B, C, D, E, G and I) in the mixture of solvents and make up to 10.0 ml with the mixture of solvents.
    Control solution (b). Dilute 1.0 ml of the test solution to 100.0 ml with the solvent mixture. Control solution (c). Dissolve 30.0 mg of methylprednisolone SCR in the solvent mixture and make up to 50.0 ml with the solvent mixture.
    Column :
    - size: l = 0.15 m, 0 = 4.6 mm;
    - stationary phase: octadecylsilylated silica gel with end cap for R chromatrography (3 μm);
    - temperature: 45 ° C.
    Mobile phase:
    - mobile phase A: phosphoric acid R, tetrahydrofuran R, acetonitrile R, water R (0.1: 1.5: 10: 90 W / W);
    - mobile phase B: phosphoric acid R, tetrahydrofuran R, acetonitrile R (0.1: 1.5: 100 W / V);
    BE2019 / 5008
    Time (min) Mobile phase A (percentV / V) Mobile phase B (percentV / V) 0 to 14 83 17 14 to 30 83 -> 52 17 -> 48
    Flow rate: 1.5 ml / min.
    Detection: spectrophotometer at 247 nm.
    Injection: 10 μL of the solution to be examined and the control solutions (a) and (b). Identification of impurities: use the Chromatogram supplied with methylprednisolone for the compliance of the SCR system and the Chromatogram obtained with the control solution (a) to identify the peaks due to impurities A, B, C, D, E, G and I.
    Relative retention compared to methylprednisolone (retention time = approximately 12 min): impurity B - approximately 0.85; impurity H - about 0.8; impurity A - about 0.92; impurities G and I - about 1.54; impurity C - about 1.7; impurity E - about 1.9; impurity D (isomer 1) - about 2.10; impurity D (isomer 2) - about 2.2.
    System compliance: control solution (a):
    -resolution: minimum 1.7 between the peaks due to impurity A and to methylprednisolone As regards the formation of impurities during storage, in certain embodiments, the pharmaceutical composition does not contain more than '' approximately 0.50% of impurity D after storage for approximately 6 months at approximately 40 ° C and approximately 75% relative humidity. Similarly, in some embodiments, the composition contains no more than about 0.30% impurity G and impurity I combined after storage for about 6 months at about 40 ° C and about 75% relative humidity.
    The invention also relates to a method of treating allergic conditions, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous system diseases, ophthalmic diseases, nephropathies, respiratory diseases, rheumatic diseases, trichinosis with neurological or myocardial involvement, or tuberculous meningitis with subarachnoid or imminent block, comprising the administration of an effective amount of a suspension described herein.
    As used herein, the term "effective amount" refers to the dosage of
    BE2019 / 5008 methylprednisolone which provides the specific pharmacological response for which methylprednisolone is administered. An "effective amount" of methylprednisolone which is administered to a particular subject in a particular case will not always be effective in the treatment of the conditions / diseases described in this document, even if such a dosage is considered to be an "effective amount" by the skilled person.
    The allergic conditions which can be treated by the administration of the suspensions described here include serious or incapacitating allergic states, difficult to treat adequately in the conventional treatment of asthma, atopic dermatitis, dermatitis, contact, hypersensitivity reactions to the drug, seasonal or perennial allergic rhinitis, serum sickness and transfusion reactions.
    The dermatological diseases which can be treated by the administration of the suspensions described here include dermatitis herpetiformis bullosa, severe psoriasis, exfoliative erythroderma, exfoliative dermatitis, severe seborrheic dermatitis, mycosis fungoides, pemphigus and l severe erythema (Stevens-Johnson syndrome).
    Endocrine disorders which can be treated by the administration of the suspensions described here include primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and non-suppurative thyroiditis.
    Gastrointestinal diseases which can be treated by administering the suspensions described here include regional enteritis and ulcerative colitis.
    Haematological disorders which can be treated by the administration of the suspensions described here include acquired hemolytic anemia (autoimmune), congenital hypoplastic anemia (erythroid) (Diamond Blackfan anemia), pure aplasia of red blood cells , idiopathic thrombocytopenic purpura, erythroblastopenia (RBC anemia) and secondary thrombocytopenia. Neoplastic diseases which can be treated by the administration of the suspensions described here include leukemias and lymphomas.
    The nervous system diseases which can be treated by the administration of the suspensions described here include acute exacerbations of multiple sclerosis; and brain edema associated with a primary or metastatic brain tumor or craniotomy.
    The ophthalmic diseases which can be treated by the administration of the suspensions described here include sympathetic ophthalmia, temporal arteritis,
    BE2019 / 5008 Allergic marginal corneal ulcers, diffuse posterior uveitis and uveitis and choroiditis, keratitis, optic neuritis, ophthalmic shingles, allergic conjunctivitis, chorioretinitis, iritis and iridocyclitis, inflammation of the anterior segment and ocular inflammatory conditions not responding to topical corticosteroids.
    Kidney diseases which can be treated by administering the suspensions described here include idiopathic nephrotic syndrome and lupus erythematosus.
    Respiratory diseases which can be treated by administering the suspensions described here include berylliosis, fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonia, Loeffler syndrome not manageable by other means, pneumonitis by symptomatic aspiration and sarcoidosis.
    Rheumatic disorders which can be treated by the administration of the suspensions described here include acute gouty arthritis, osteoarthritis synovitis, post-traumatic osteoarthritis, non-specific acute tenosynovitis, epicondylitis, acute rheumatic carditis, rheumatoid arthritis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, polymyositis, acute and subacute bursitis and systemic lupus erythematosus.
    The subject to which the suspensions can be administered is generally a human being. Human beings can be of any age. However, in some embodiments, the human to whom the pharmaceutical composition is administered is a child or an infant. In various embodiments, the child or infant is less than 16 years old, less than 12 years old, less than 8 years old, less than 6 years old, less than 4 years old or less than 2 years old. In other embodiments, the human to whom the pharmaceutical composition is administered is a geriatric subject. In various embodiments, the geriatric subject is at least 65 years of age, at least 70 years of age, or at least 75 years of age.
    Examples The results of the stability studies carried out by the International Council for the Harmonization of Technical Requirements for Pharmaceutical Products for Human Use (ICH) on the oral suspension of methylprednisole (10 mg / 5 ml and 16 mg / 5 ml ) packaged in amber glass bottles are shown below. A batch of suspension laboratory tests
    BE2019 / 5008 oral methylprednisolone (16 mg / 5 ml) ("Suspension A") was tested for stability. Another batch of laboratory tests of methylprednisolone oral suspension (10 mg / 5 ml) ("Suspension B") was also tested for stability.
    The test of the suspension A was carried out according to the following stability protocol:
    CONDITION TEST INTERVALS (in months) 0 1 2 3 4 5 6 LONG TERM25 ° C ± 2 ° C / 60% RH ± 5% X xXX X INTERMEDIATE30 ° C ± 2 ° C / 65% RH ± 5%XXX X ACCELERATED40 ° C ± 2 ° C / 75% RH ± 5%XXX X
    METHODS TEST INTERVALS (in months) 0 1 2 3 4 5 6 Homogeneity of the suspension X X X MTP dosing X XXX X Methylparanene dosage X XXX X Related substances X XXX X Dissolution X X X XRD XX Antimicrobial efficacy test (AET) X
    The tests for suspension B were carried out in accordance with the following stability protocol:
    CONDITION TEST INTERVALS (in months) 0 1 2 3 4 5 6 LONG TERM25 ° C ± 2 ° C / 60% RH ± 5% X X X X X X X ACCELERATED40 ° C ± 2 ° C / 75% RH ± 5% X X X X X X X
    METHODS TEST INTERVALS (in months) 0 1 2 3 4 5 6 Homogeneity of the suspension X X X MTP dosage X X X X X X X Methylparanene dosage X X X X X X X Related substances X X X X X X X Dissolution X X X X X X X Antimicrobial efficacy test (AET) X
    BE2019 / 5008 The respective lots had the following compositions:
    Suspension B Suspension A Methylprednisolone 0.20 0.32 Sucralose 0.70 0.70 Tutti Frutti 77919-33 Givaudan 0.12Peppermint aroma0.12 Masking flavor 4626 IFF 0.10 0.10 Sodium methylparaben 0.20 0.20 Saccharin sodium 0.20 0.20 Xanthan gum FF 0.23 0.23 Anhydrous citric acid 0.18 0.18 Trisodium citrate 0.20 0.20 Purified water 97.87 97.75 Total (g) 100.00 100.00
    The analytical method for related substances in the oral suspension of methylprednisolone was developed on the basis of the analytical method for related substances described in the monograph of the European Pharmacopoeia, eighth edition, volume 2 (2013) on methylprednisolone (p. 2748-2750), which is incorporated herein by reference in its entirety.
    Impurity D: Impurity D is defined here and in some embodiments is limited to 0.5%. Impurity A: Impurity A is defined here and in some embodiments is limited to 0.3%.
    Impurities G and I: Impurities G and I are defined here and in some embodiments are limited to 0.3% collectively (i.e. the sum of impurities G and I does not exceed 0.3% ).
    Impurities C, E and F: Impurities C, E and F are defined here and in certain embodiments are limited to 0.15%. This limit corresponds to the qualification threshold for degradation products in accordance with ICH chapter Q 3 A (R2), “Impurities in new medicinal substances”, as well as the maximum daily dose (1 g of medicinal substance) in the drug product SPC (FI). The limits for impurities C, E and F are defined in accordance with Chapter Q 3 B (R2) of the ICH “Impurities in New Drugs”, as well as the maximum daily dose in the SPC drug product (FI). Given the above information: The
    BE2019 / 5008 identification threshold is 0.20%. The qualification threshold is 0.20%.
    Any other impurity: Any other impurity includes all the other detectable, potential and specified impurities (J, K and L) which are defined here. Any other impurities also include any unknown / unspecified impurities presented in the drug product. The limits are established in accordance with Chapter Q 3 B (R2) of the ICH “Impurities in New Drug Products”, as well as the maximum daily dose in the SPC of the drug product (FI). Given the above information: The identification threshold is 0.20%.
    Compound RRt EP imp. B 0.85 EP imp. H 0.88 EP imp. AT 0.94 Methylprednisolone 1.00 EP imp. F 1.09 EP imp. G and I 1.59 EP imp. VS 1.77 EP imp. E 1.95 EP imp. D (isomer 1) 2.10 EP imp. D (isomer 2) 2.21
    The homogeneity of the suspension was determined by the test described above, taken from the British Pharmacopoeia (2008), which is incorporated here by reference in its entirety.
    The stability results for the respective batches are as follows in Tables 1 to 5:
    BE2019 / 5008
    Table 1
    Long-term stability results for suspension A (storage conditions:
    25 ° C +/- 2 ° C, relative humidity - 60 +/- 5%)
    Test Specification 0 months 1 month 2 months 3 months 4 months 5 months 6 months Homogeneity of the suspension Each individual dose represents between 85% and 115% of the average dose 100.8 - - 101.7 104.3 Dosagemethylprednisolone 95.0% 105.0% of the label 100.4 101.3 - 101.3 103.4 Methylparaben dosage 70.0% -110.0% 105.6 106.9 - 107.3 109.6 Related substances: Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F Sum of imp. G etlImpurity HAny other imp.Total impurities NMT 0.30%NMT 0.20%NMT 0.20%NMT 0.50%NMT 0.20%NMT 0.20%NMT 0.30%NMT 0.20%NMT 0.20%To define 0.060.07 BRT0.07 BRT*BRT+0.06 (RRT1.51)0.26 0.070.07 BRT0.12BRT*BRTBRT0.26 - 0.060.08 BRT0.13BRT ndBRTBRTBRT0.27 0.060.06 BRT0.150.12 nd0.05BRT 0.09 (RRT 1.45) 0.06 (RRT 1.71)0.59 Dissolution NLT 80% (Q) of the labeled amount of C22H30O5 is dissolved in 30 minutes 102.5 - - 101.9 101.8 XRD - AET Ph. Eur. 5.1.3(oral prep) -
    Table 2
    Intermediate stability results for suspension A (storage conditions:
    30 ° C +/- 2 ° C, relative humidity = 65 +/- 5%)
    Test Specification 0 months 1 month 2 months 3 months 4 months 5 months 6 months Homogeneity of the suspension Each individual dose represents between 85% and 115% of the average dose 100.8 - - 101.6 103.5 Dosagemethylprednisolone 95.0% 105.0% of the label 100.4 101.0 - 100.3 102.1 Methylparaben dosage 70.0% -110.0% 105.6 107.0 - 108.0 109.5 Related substances: Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F NMT 0.30%NMT 0.20%NMT 0.20%NMT 0.50%NMT 0.20%NMT 0.20% 0.060.07 BRT0.07 BRT* 0.060.07 BRT0.13BRT* - 0.060.07 BRT0.14BRT ND 0.070.07 BRT0.220.15ND
    BE2019 / 5008
    Sum of imp. G and I NMT 0.30% BRT 0.060.08 0.06 Impurity H N MT 0.20% * *BRT BRT 0.15 (RRT 1.46) Any other imp. NMT 0.20% 0.06 (RRT BRTBRT 0.08 (RRT 1.51) 1.71) Total impurities To define 0.26 0.320.35 0.80 Dissolution N LT 80% (Q) of the labeled amount of C22H30O5 is dissolved in 30 minutes 102.5 - - 101.9 100.9 XRD To define -
    Table 3
    Accelerated stability results for suspension A (storage conditions: 40 ° C +/- 2 ° C, relative humidity - 75 +/- 5%)
    Test Specification 0 months 1 month 2 months 3 months 4 months 5 months 6 months Homogeneity of the suspension Each individual dose represents between 85% and 115% of the average dose 100.8 - - 100.6 102.8 Dosagemethylprednisolone 95.0% 105.0% of the label 100.4 101.3 - 100.9 102.6 Methylparaben dosage 70.0% -110.0% 105.6 106.7 - 107.9 109.3 Related substances: Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F Sum of lmp. G and I NMT 0.30%NMT 0.20%NMT 0.20%NMT 0.50%NMT 0.20%NMT 0.20 7oNMT 0.30% 0.060.07 BRT0.07 BRT*BRT 0.060.07 BRT0.18 BRT*0.150.060.08 BRT0.19 BRTND0.31 0.050.08 BRT0.160.18 ND0.23 Impurity H NMT 0.20% * * - BRT BRT0.54 (RRT1.46) Any other imp. NMT 0.20% 0.06 (RRT 1.51) 0.05 (RRT1.65)0.05 (RRT1.86)0.05 (RRT 1.69)0.14 (RRT 1.91) 0.07 (RRT1.71)0.05 (RRT1.85) Total impurities To define 0.26 0.560.83 1.36 Dissolution NLT 80% (Q) of the labeled amount of C22H30O5 is dissolved in 30 minutes 102.5 - - 103.4 101.4 XRD -
    BE2019 / 5008
    Table 4
    Long-term stability results for suspension B (storage conditions:
    25 ° C +/- 2 ° C, relative humidity - 60 +/- 5%)
    Test Specification 0 months 1 month 2 months 3 months 4 months 5 months 6 months Homogeneity of the suspension Each individual dose represents between 85% and 115% of the average dose 104.2% 100.9% Dosagemethylprednisolone 95.0% 105.0% of the label 102.8% 102.8% 101.6% 101.1% 100.6% Methylparaben dosage 70.0% -110.0% 95.9% 96.5% 96.2% 96.3% 95.3% Related substances: Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F Sum of lmp. G etlImpurity H Any other lmp.Total impurities NMT 0.30%NMT 0.20%NMT 0.20%NMT 0.50%NMT 0.20%NMT 0.20%NMT 0.30%NMT 0.20%NMT 0.20%To define BRT BRT BRT BRT 0.05 NDBRTBRT0.06(RRT1.78)0.11% BRT0.05BRTBRTBRTBRTBRTBRT0.11 (RRT 2.26)0.16% BRT0.050.080.23 BRT BRTBRTBRT 0.06 (RRT 1.43)0.42% BRT0.050.050.18 BRT BRT0.10BRT0.38% BRT0.050.050.18 BRT BRT0.11BRT0.39% Dissolution NLT 80% (Q) of the labeled amount of C22H30O5 is dissolved in 30 minutes 94.6% 93.5% 92.8% 91.0% 89.7% PH 4.0 - 6.0 4.85 5.05 5.05 5.04 5.05 AET Ph. Eur. 5.1.3 (oral prep)
    Table 5
    Accelerated stability results for suspension B (storage conditions: 40 ° C +/- 2 ° C, relative humidity - 75 +/- 5%)
    Test Specification 0 months 1 month 2 months 3 months 4 months 5 months 6 months Homogeneity of the suspension Each individual dose represents between 85% and115% of the average dose 104.2% F: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·:: ·:99.3% Dosagemethylprednisolone 95.0% 105.0% of the label 102.8% 102.0% 101.5% 101.1% 99.8% Methylparaben dosage 70.0% -110.0% 95.9% 96.8% 96.2% 96.3% 95.2% Related substances: Impurity A Impurity B Impurity C NMT 0.30%NMT 0.20%NMT 0.20% BRTBRTBRT BRT0.05BRT BRT0.050.08 BRT0.060.05 BRT0.070.05
    BE2019 / 5008
    Impurity DImpurity EImpurity FSum of imp. G etlImpurity HAny other imp.Total impurities N MT 0.50%NMT 0.20%NMT 0.20%NMT 0.30%NMT 0.20%NMT 0.20%To define BRT0.05NDBRTBRT0.06(RRT1.78)0.11% 0.05 BRT BRT0.17BRT0.20 (RRT 2.26)0.47% 0.33 BRT BRT0.06BRT0.29(RRT1.43)0.81% 0.250.13 BRT0.47BRT0.96% 0.250.19 BRT0.59BRT1.15% Dissolution NLT 80% (Q) of the labeled amount of C22H30O5 is dissolved in 30 minutes 94.6% 91.5% 92.2% 89.1% 89.4% PH 4.0 - 6.0 4.85 5.11 5.06 5.03 5.02 AET Ph. Eur. 5.1.3(oral prep)
    The homogeneity of a 50 ml methylprednisolone suspension is determined by allowing the suspension to settle without being disturbed for 24 hours. The container containing the 50 ml suspension is then stirred for 30 seconds. A 5 ml dose is taken at a depth of 1 cm below the meniscus. The container containing the remaining 45 ml of suspension is again stirred for 10 seconds and another 5 ml dose is withdrawn. This procedure is repeated until the ten 5 ml doses of the suspension have been withdrawn. The ten doses are dosed individually according to the following procedure:
    DOSAGE
    Dissolve 0.100 g in alcohol R and make up 100.0 ml with the same solvent. Dilute 2.0 ml of the solution to 100.0 ml with alcohol R. Measure the absorbance (2.2.25) at maximum at 243 nm.
    Calculate the content of C22H30O5 by taking the specific absorbance at 395.
    The suspension is homogeneous if each 5 ml dose represents between 85% and 115% of the average dose. The suspension is not homogeneous if more than one individual dose of 5 ml does not represent between 85% and 115% of the average dose, or if an individual dose of 5 ml is outside the limits of 75% to 125 % of the average content.
    权利要求:
    Claims (25)
    [1]
    1. A premixed aqueous suspension for oral administration comprising from about 2 mg / ml to about 4 mg / ml of methylprednisolone, wherein the suspension has a shelf life of at least about 12 months when stored at about 25 ° C and about 60% relative humidity.
    [2]
    2. The suspension according to claim 1, comprising approximately 3 mg / ml to approximately 4 mg / ml of methylprednisolone.
    [3]
    3. The suspension according to claim 2, comprising approximately 3.2 mg / ml of methylprednisolone.
    [4]
    4. The suspension according to claim 1, wherein the suspension is homogeneous.
    [5]
    5. The suspension according to claim 1, in which the methylprednisolone is micronized.
    [6]
    6. The suspension according to claim 5, wherein the diameter of at least 90% of the micronized methylprednisolone is from about 12 to about 15 micrometers.
    [7]
    7. The suspension according to claim 4, in which the suspension is homogeneous after storage at approximately 25 ° C and at approximately 60% relative humidity for approximately one year.
    [8]
    8. The suspension according to claim 4, wherein the suspension is homogeneous after storage at about 25 ° C and about 60% relative humidity for about 24 months.
    [9]
    9. The suspension according to claim 1, wherein the suspension has a shelf life of at least about 24 months.
    [10]
    10. The suspension according to claim 1, wherein the suspension has a shelf life of at least about 36 months.
    BE2019 / 5008
    [11]
    11. The suspension of claim 1, wherein the pH of the suspension is from about 4.0 to about 6.0.
    [12]
    12. The suspension of claim 11, wherein the pH of the suspension is from about 5.0 to about 5.5.
    [13]
    13. A premixed aqueous suspension for oral administration comprising:
    about 2 mg / ml to about 4 mg / ml methylprednisolone;
    a sweetener in an amount of from about 0.1% by weight to about 2.0% by weight;
    a preservative in an amount of from about 0.05% by weight to about 1.0% by weight;
    a suspending agent in an amount of from about 0.05% by weight to about 2.0% by weight;
    a buffering agent in an amount of from about 0.05% by weight to about 1.0% by weight;
    a flavoring agent in an amount of from about 0.05% by weight to about 1.0% by weight; and a taste masking agent in an amount of from about 0.01% by weight to about 1.0% by weight, wherein the suspension has a shelf life of at least about 12 months when stored at about 25 ° C and a relative humidity of about 60%.
    [14]
    14. The suspension according to claim 13, comprising approximately 3.2 mg / ml of methylprednisolone.
    [15]
    15. The suspension according to claim 13, in which the sweetener is chosen from sucralose, saccharin sodium and a combination thereof.
    [16]
    16. The suspension according to claim 13, in which the preservative is methylparaben sodium.
    [17]
    17. The suspension according to claim 13, wherein the suspending agent is xanthan gum.
    [18]
    18. The suspension according to claim 13, in which the buffering agent is chosen
    BE2019 / 5008 among citric acid, sodium citrate and a combination thereof.
    [19]
    19. The suspension according to claim 13, in which the flavoring agent is a tutti frutti flavoring agent.
    [20]
    20. The suspension according to claim 13, wherein the taste-producing agent comprises monoammonium glycyrrhizinate, sucralose and maltodextrin.
    [21]
    21. A premixed aqueous suspension for oral administration comprising from about 2 mg / ml to about 4 mg / ml of methylprednisolone, in which the suspension retains at least 90% of the released amount of methylprednisolone after storage at about 25 ° C and about 60 % relative humidity for about six months.
    [22]
    22. The suspension according to claim 21, comprising approximately 3.2 mg / ml of methylprednisolone.
    [23]
    23. The suspension of claim 21, wherein the suspension retains at least about 90% of the amount of methylprednisolone released after storage at about 25 ° C and about 60% relative humidity for about 12 months.
    [24]
    24. The suspension according to claim 21, wherein the suspension contains not more than about 0.50% impurity D after storage of about 6 months at about 40 ° C and about 75% relative humidity.
    [25]
    25. The suspension of claim 21, wherein the suspension contains not more than about 0.30% of impurity G and impurity I combined after storage for 6 months at about 40 ° C and about 75 % relative humidity.
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    同族专利:
    公开号 | 公开日
    US20190216823A1|2019-07-18|
    BE1025934A1|2019-08-09|
    引用文献:
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    法律状态:
    2020-08-03| FG| Patent granted|Effective date: 20200505 |
    优先权:
    申请号 | 申请日 | 专利标题
    US201862616556P| true| 2018-01-12|2018-01-12|
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