Immediate release oral pharmaceutical formulations of escitalopram or its racemate with increased API content

Abstract

The present invention provides an immediate release oral pharmaceutical composition comprising, by weight, 60.1% or more citalopram oxalate or escitalopram oxalate, or 25.1% or more citalopram oxalate or escitalopram oxalate with a median particle size greater than 40 μm, and 0% to 74.9% additional pharmaceutical excipients.

Description

[Technical Field]

[0001] The present invention provides an immediate-release oral pharmaceutical composition comprising, by weight, at least 60.1% escitalopram oxalate or at least 25.1% escitalopram oxalate (median particle size greater than 40 μm) and 0% to 74.9% additional pharmaceutical excipients. The instant-release oral escitalopram oxalate formulations prepared using the invented composition have the advantages of a higher API content and a lower excipient content while meeting pharmaceutical quality requirements. Escitalopram oxalate also includes other pharmaceutically acceptable salts of escitalopram, as well as the racemate (citalopram) and its pharmaceutically acceptable salts.

[0002] The present invention is in the field of pharmaceutical formulations, compositions of matter, compositions of escitalopram or its racemate, immediate release oral formulations. [Background technology]

[0003] Escitalopram is an antidepressant in the selective serotonin reuptake inhibitor (SSRI) class.

[0004] Escitalopram and its racemic form (citalopram) are used to treat depression and generalized anxiety disorder (GAD). They are antidepressants that belong to a group of medications known as selective serotonin reuptake inhibitors (SSRIs). These medications work by increasing the activity of the chemical serotonin in the brain.

[0005] Escitalopram is typically administered in the form of escitalopram oxalate, either as immediate-release film-coated tablets (e.g., Cipralex) or extended-release tablets. A typical commercially available film-coated escitalopram tablet contains approximately 11% escitalopram oxalate. Standard doses are 5 mg, 10 mg, 15 mg, and 20 mg, and the usual dosage form is a film-coated tablet. Escitalopram film-coated tablets are typically and optionally packaged in PVC / ALU or ALU / ALU blisters to ensure product stability.

[0006] Citalopram is typically administered in the form of escitalopram hydrobromide as immediate-release film-coated tablets (e.g., Cipramil). Typical commercially available film-coated citalopram tablets contain approximately 20% citalopram hydrobromide. Standard doses are 10 mg, 20 mg, 30 mg, and 40 mg. Film-coated citalopram tablets are also typically and optionally packaged in PVC / ALU or ALU / ALU blisters to ensure product stability.

[0007] Pharmaceutical packaging has a significant environmental impact. This is because the aluminum and plastic that make up blister packs are difficult, and in some cases impossible, to recycle effectively due to their tightly packed nature. Reseparating these materials requires a significant amount of energy, and even then, the resulting aluminum is not of the same high quality as virgin aluminum. Larger immediate-release oral pharmaceutical dosage forms necessitate larger primary packaging, resulting in more waste material.

[0008] Additionally, there is an environmental burden caused by the extensive transportation steps required for the finished product, for example, from the manufacturer to the wholesaler and from there to the pharmacy. In the pharmaceutical industry, each box of finished product must undergo multiple transportation steps before reaching the customer, often including international routes. This is particularly true for generic drugs, and even more so for products sold in large volumes, such as escitalopram. The volume of the finished product is a factor in determining the efficiency of transportation and storage, as a larger volume product requires more space and more frequent transportation than a smaller volume version of the same product.

[0009] Furthermore, if possible, patient exposure to excipients should be avoided. Immediate-release oral formulations are administered to expose the human body to the drug, not to the excipients. For the pharmaceutical industry, using excipients in products where their use can be avoided, especially in large quantities, is a waste of resources. Furthermore, the global demand for excipients is increasing, and the chemical industry's supply capacity is not keeping up with the demand, further exacerbating this waste of resources.

[0010] Previously patented escitalopram tablet formulations, such as WO2009150665 and WO2018190294, have achieved escitalopram weight contents of 25.0% and 10.2%, respectively. A maximum escitalopram content of 60.0% has been confirmed in European Patent EP2086509, provided the median particle size of escitalopram is less than 40 μm. Escitalopram, the racemic form of escitalopram, has been achieved at 60.0% in EP1318805A2, but this also requires the median particle size of citalopram to be less than 40 μm in order to function. A 2014 dissertation by Aravapalli VSA Kumar (Aravapalli, VSA Formulation and Evaluation of Escitalopram Oxalate Immediate Release Tablets. 2014. Dissertation. College of Pharmacy, Jaya College of Paramedical Sciences, Chennai) describes a compatibility study for escitalopram oxalate, in which a powder blend of the API (potentially containing excipients) was filled into vials and analyzed using an excipient compatibility test. A method for preparing 20 mg escitalopram tablets is also described, but these differ in composition from the powder blend and do not contain increased active ingredient concentrations. Tablets or capsules with increased active ingredient concentrations are not described. Summary of the Invention

[0011] We have surprisingly found a method for producing an immediate-release oral pharmaceutical formulation having a high escitalopram content, and have also surprisingly found that the particle size limitation that was previously thought to be necessary for achieving a high escitalopram content is not actually necessary. The present invention demonstrates that it is possible to achieve an escitalopram content of 25.0% or more with a median particle size of more than 40 μm, and that the escitalopram content can be increased to 60.0% or more.

[0012] Currently, film-coated tablets of escitalopram 5 mg weigh approximately 60 mg, and film-coated tablets of escitalopram 20 mg weigh approximately 240 mg. The excipient content is 54 mg and 214 mg, respectively, for film-coated tablets. According to the present invention, the excipient content can be reduced to 0% for tablet formulations, and to approximately 3% for film-coated tablets, even when the coating is taken into account.

[0013] Because the amount of excipients required is reduced to a minimum, immediate-release oral pharmaceutical formulations are smaller, resulting in a corresponding reduction in blister size and therefore the overall size of the finished product. Smaller blisters than previously possible can now be used, allowing the finished product to be just a fraction of its current volume. This results in significantly improved shipping efficiency and a reduced carbon footprint for the product. Additionally, minimal packaging waste is generated.

[0014] It also reduces the amount of excipients administered to patients to essential amounts and significantly relieves the pharmaceutical industry from having to source and process unnecessarily large amounts of excipients.

[0015] Because escitalopram is a high-volume prescription drug, it is synthesized in numerous manufacturing plants and the finished product is manufactured worldwide. The facilities and equipment required to carry out the production of the prescribed formulations are readily available. The following compositions and preparations are feasible for any manufacturing site that intends to manufacture tablets. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a graph showing representative results of the dissolution tests in the following examples. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0017] Example 1 - Preparation of escitalopram film-coated tablets

[0018] Step 1: Pass excipients, if present, or excipients as shown in Tables 1 to 6 (amounts adjusted according to desired batch size) through a suitable screen. For the avoidance of doubt, "screen" as used herein refers to a sieve preferably having a pore size of between 250 μm and 710 μm.

[0019] Step 2: All excipients are mixed in a blender along with the API. For the avoidance of doubt, citalopram oxalate or escitalopram oxalate is added as apparent in light of the table below; this may be added in Step 1 or Step 2.

[0020] Step 3: The lubricant is usually added last and mixed.

[0021] Step 4: The final mixture is compressed into tablets.

[0022] Step 5: The tablets may be film coated.

[0023] Such preparation methods include, but are not limited to, direct compression and wet granulation.

[0024] Example Composition

[0025] Table 1- Composition example 1 [Table 1]

[0026] Table 2 - Composition example 2 [Table 2]

[0027] Table 3 - Composition Example 3 [Table 3]

[0028] Table 4 - Composition Example 4 [Table 4]

[0029] The median particle size is measured specifically using a Retsch analytical woven wire mesh sieve (mesh size 40 μm).

[0030] Table 5 - Composition Example 5 [Table 5]

[0031] Example 2 - Examples of tablet weights with different compositions

[0032] Table 6 - Summary of Tablet Weight Examples [Table 6]

[0033] Example 3 - Analytical Results

[0034] Table 7 - Disintegration time and shatter resistance [Table 7]

[0035] Dissolution testing was performed on the tablets of Example 3 in 900 ml of pH 6.8 buffer at 37°C and 100 rpm in USP Apparatus 1. The resulting dissolution curves show that the tablets dissolved rapidly and completely within 30 minutes.

[0036] The quality qualification of the immediate release oral pharmaceutical formulation prepared according to the present invention is compliant as it meets the requirements of the USP monograph for escitalopram tablets.

[0037] Specific embodiments of the present invention are listed below:

[0038] 1. A pharmaceutical composition for an immediate-release oral pharmaceutical formulation, comprising, by weight, 60.1% or more escitalopram oxalate or 25.1% or more escitalopram oxalate (median particle size of 40 μm or more) and 0% to 74.9% additional pharmaceutical excipients, more preferably 70.1% or more escitalopram oxalate or 30.1% or more escitalopram oxalate (median particle size of 40 μm or more), and even more preferably 75.1% or more escitalopram oxalate or 60.1% or more escitalopram oxalate (median particle size of 40 μm or more).

[0039] 2. Escitalopram oxalate according to item 1, which also includes other pharmaceutically acceptable salts of escitalopram.

[0040] 3. Escitalopram oxalate according to item 1, which also includes the racemate (citalopram) and pharmaceutically acceptable salts thereof.

[0041] 4. Pharmaceutical excipients according to item 1, consisting of, but not limited to, one or more disintegrants, lubricants, fillers, glidants.

[0042] 5. Disintegrants according to item 4, consisting of, but not limited to, microcrystalline cellulose, sodium alginate, croscarmellose sodium, crospovidone and any superdisintegrant.

[0043] 6. The fillers according to item 4, consisting of, but not limited to, cellulose, lactose, mannitol, starch, sucrose and calcium phosphate.

[0044] 7. The lubricant according to item 4, consisting of, but not limited to, calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0045] 8. Lubricants as described in item 4, consisting of, but not limited to, silica derivatives, talc and corn starch.

[0046] 9. An immediate release oral pharmaceutical form according to item 1, including, but not limited to, tablets, film-coated tablets and capsules, but also including other types of immediate release dosage forms. In the case of film-coated tablet or capsule forms, the weight % of escitalopram or racemate (citalopram) refers to the weight of API of the entire pharmaceutical form (e.g., including film coating and capsule shell).

[0047] 10. The pharmaceutical composition according to item 1, characterized in that the dosage range of escitalopram or racemate (citalopram) is 1.25 mg to 40 mg.

[0048] Further embodiments of the present invention are listed below: 1. An immediate release oral pharmaceutical composition comprising, by weight: a) 60.1% or more of citalopram oxalate or escitalopram oxalate, or b) 25.1% or more of escitalopram oxalate or escitalopram oxalate (median particle size 40 μm or more), and 0% to 74.9% of one or more additional pharmaceutical excipients; 1. An immediate release oral pharmaceutical composition comprising:

[0049] In a preferred embodiment, the immediate release oral pharmaceutical composition does not contain any further active ingredient other than citalopram oxalate or escitalopram oxalate, i.e., the immediate release oral pharmaceutical composition contains, for example, 60.1% or more by weight of the active ingredient (or other proportions or amounts as further detailed in the specification), wherein the active ingredient is citalopram oxalate or escitalopram oxalate.

[0050] 2. The immediate release oral pharmaceutical composition according to item 1, a) the amount of citalopram oxalate or escitalopram oxalate is 70.1% or more, preferably 75.1% or more by weight; or b) The immediate release oral pharmaceutical composition, wherein the amount of escitalopram oxalate or escitalopram oxalate (median particle size of 40 μm or more) is 30.1% or more, preferably 60.1% or more.

[0051] In another embodiment, the amount of citalopram oxalate or escitalopram oxalate in the immediate release oral pharmaceutical composition is 75% or more by weight, more preferably 98.5% or more, even more preferably 100%.

[0052] 3. The immediate release oral pharmaceutical composition according to item 1 or 2, wherein the additional pharmaceutical excipients comprise one or more components selected from the group comprising disintegrants, lubricants, fillers and glidants.

[0053] 4. The immediate release oral pharmaceutical composition according to item 3, wherein the disintegrant is one or more disintegrants selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, carboxymethylcellulose, alginic acid, sodium alginate and its derivatives, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (such as Ac Di Sol®, Solutab®, Vivasol®), crospovidone (such as Kollidon®, Kollicoat®), other superdisintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.

[0054] 5. The immediate release oral pharmaceutical composition according to item 3 or 4, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.

[0055] Those skilled in the art will recognize that certain excipients used as fillers can also function as disintegrants. For example, cellulose, lactose, mannitol, starch, sucrose, etc. In embodiments in which any of these is included as a disintegrant, it is not additionally used as a filler. In other words, in embodiments of the present invention, being included as a "disintegrant" or a "filler" is mutually exclusive.

[0056] 6. The composition according to any one of items 3 to 5, wherein the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0057] 7. The immediate release oral pharmaceutical composition according to any one of items 3 to 6, wherein the lubricant is one or more lubricants selected from the group comprising silica derivatives (e.g., silicon dioxide), talc, and corn starch.

[0058] 8. An immediate release oral pharmaceutical composition according to any of items 1 to 7, in tablet or film-coated tablet form, wherein the weight percentages in said film-coated tablet form refer to the weight of the entire pharmaceutical composition, including the film coating weight of the tablet core.

[0059] 9. The immediate release oral pharmaceutical composition according to any of items 1 to 8, wherein citalopram oxalate or escitalopram oxalate is contained in a dosage range of 1.25 mg to 40 mg, particularly 1.25 mg to 20 mg, or 1.25 mg to 5 mg, more particularly 5 mg to 20 mg.

[0060] 10. A method for preparing a tablet comprising the immediate release oral pharmaceutical composition according to any one of items 1 to 9, comprising: The method comprises: a) passing one or more pharmaceutical excipients through a sieve; b) mixing said one or more pharmaceutical excipients; c) optionally adding a lubricant to the mixture of b) and mixing; d) compressing the mixture obtained from c) into tablets; and e) optionally applying a film coating to said tablets; Including, wherein the citalopram oxalate or escitalopram oxalate is added either during step a) or between steps b) and c); the weight amounts and dosage ranges of the excipients and citalopram oxalate or escitalopram oxalate in the resulting tablets are as defined in the preceding paragraphs; The method.

Claims

1. 1. An immediate release oral pharmaceutical composition comprising, in weight percent: a) 60.1% or more of citalopram oxalate or escitalopram oxalate, or b) 25.1% or more of citalopram oxalate or escitalopram oxalate with a median particle size greater than 40 μm; and one or more additional pharmaceutical excipients in a weight percentage ranging from 0% to 74.9%.

2. a) the amount of citalopram oxalate or escitalopram oxalate is greater than or equal to 70.1%, preferably greater than or equal to 75.1%; or b) the amount of citalopram oxalate or escitalopram oxalate in the median particle size greater than 40 μm is 30.1% or more, preferably 60.1%; 10. The immediate release oral pharmaceutical composition of claim 1.

3. 3. The immediate release oral pharmaceutical composition of claim 1, wherein the additional pharmaceutical excipients comprise one or more components selected from the group comprising disintegrants, lubricants, fillers, and glidants.

4. 4. The immediate release oral pharmaceutical composition of claim 3, wherein the disintegrant is one or more disintegrants selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, carboxymethylcellulose, alginic acid, sodium alginate and derivatives thereof, sodium starch glycolate (e.g., Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (e.g., Ac Di Sol®, Solutab®, Vivasol®), crospovidone (e.g., Kollidon®, Kollicoat®) and other superdisintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.

5. 5. The immediate release oral pharmaceutical composition of claim 3 or 4, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.

6. 6. The immediate release oral pharmaceutical composition according to any one of claims 3 to 5, wherein the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate and magnesium lauryl sulfate.

7. 7. The immediate release oral pharmaceutical composition according to any one of claims 3 to 6, wherein the lubricant is one or more lubricants selected from the group comprising silica derivatives, talc and corn starch.

8. 8. The immediate release oral pharmaceutical composition according to any one of claims 1 to 7, in tablet form or film-coated tablet form, wherein the weight percentages in said film-coated tablet form refer to the weight of the entire pharmaceutical composition, including the film coating weight of the tablet core.

9. 9. An immediate release oral pharmaceutical composition according to any one of claims 1 to 8, wherein citalopram oxalate or escitalopram oxalate is contained in a dosage range of 1.25 mg to 40 mg, particularly 1.25 mg to 20 mg, or 1.25 mg to 5 mg, more particularly 5 mg to 20 mg.

10. A method for preparing a tablet comprising the immediate release oral pharmaceutical composition of any one of claims 1 to 9, comprising: The method comprises: a) passing one or more pharmaceutical excipients through a sieve; b) mixing said one or more pharmaceutical excipients; c) optionally adding a lubricant to the mixture of b) and mixing; d) compressing the mixture obtained from c) into tablets; and e) optionally applying a film coating to the tablets; Including, wherein the citalopram oxalate or escitalopram oxalate is added either during step a) or between steps b) and c); The weight amounts and dosage ranges of the excipients and citalopram oxalate or escitalopram oxalate in the resulting tablets are as defined in the preceding claims. The method.

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