Pharmaceutical composition comprising ramelteon and nasal administration formulation

Abstract

The present invention relates to a pharmaceutical composition comprising ramelteon and a nasal administration formulation. The pharmaceutical composition comprises ramelteon and polyethylene glycol. The pharmaceutical composition of the present invention has high stability and can be used to prepare a pharmaceutical formulation that meets the specifications for nasal administration formulations. Compared with oral tablets, the pharmaceutical composition of the present invention features improved bioavailability of ramelteon and a targeted concentration in brain tissue.

Description

A pharmaceutical composition containing ramelteamide and a nasal administration formulation Technical Field

[0001] This invention relates to a pharmaceutical composition containing ramelteamide and a nasal administration formulation. Background Technology

[0002] The overall prevalence of insomnia in China is 15.0%. Chronic insomnia affects an individual's normal life and work, increasing the risk of various health problems. Severe sleep deprivation can reduce work efficiency and alertness, and may even lead to serious accidents causing significant losses. Intervention methods for insomnia mainly include drug therapy, psychotherapy, physical therapy, and traditional Chinese medicine.

[0003] The 2017 Chinese Guidelines for the Diagnosis and Treatment of Insomnia recommend melatonin receptor agonists (such as rameltein) as the first-line treatment. Rameltein selectively activates melatonin receptors type 1 (MT1) and type 2 (MT2) in the brain, increasing slow-wave sleep (SWS) and rapid eye movement (REW) sleep. It is used to treat insomnia with difficulty falling asleep as the primary complaint and insomnia caused by circadian rhythm disorders. Rameltein has a low incidence of side effects and is the first non-addictive insomnia treatment drug not listed as a specially controlled substance. Because it does not cause drug dependence or withdrawal symptoms, it has been approved for long-term treatment of insomnia.

[0004] Rametamide exhibits high MT1 / MT2 receptor agonist activity in vitro (EC50 < 1 nM), but due to its short half-life [JClin Sleep Med 3(5):495–504], its distribution in the brain is minimal, affecting its full efficacy. Currently, rametamide is marketed as a tablet developed by Takeda Pharmaceutical Company of Japan under the brand name "ROZEREM". However, this drug shows a strong first-pass effect after oral administration, with an absolute bioavailability of only 1.8%. Chinese invention patent CN104224741B discloses a conventional tablet preparation method that improves the dissolution rate and stability of rametamide by micronization and the addition of antioxidants. Patent CN113274365A provides a rametamide immediate-release and sustained-release dual-release formulation, which rapidly exerts its efficacy and prolongs the duration of drug action. Both of these preparation methods involve oral administration, with the drug primarily absorbed through the digestive tract, resulting in a first-pass effect. CN112190555B discloses a method for preparing rameltetinamide sublingual tablets. Sublingual administration can avoid the first-pass effect in the liver and improve bioavailability. However, this invention does not include research on brain-targeted concentrations, and sublingual administration requires the patient to correctly place the drug under the tongue, which is a high-skill procedure.

[0005] Nasal formulations offer clinical advantages such as rapid absorption and onset of action, high bioavailability, avoidance of the first-pass effect in the liver, and higher patient compliance. Nasal formulations can bypass the blood-brain barrier via the olfactory nerve or branches of the trigeminal nerve to directly administer medication to the central nervous system, providing a relatively safer, more effective, and convenient route of administration for the treatment of brain or central nervous system diseases. However, current research on ramelteamide primarily focuses on tablet or sublingual administration, with limited research on nasal sprays. This is likely because nasal sprays have stricter requirements regarding drug properties, needing to be easily dispensed from the nasal spray device, and the poor water solubility of ramelteamide makes the preparation of nasal sprays more difficult. This also explains why nasal administration formulations have different requirements compared to oral and sublingual administration.

[0006] CN110996938A discloses a nasal spray or drop for intranasal application, or a sublingual spray or solid dosage form formulated for sublingual application, specifically comprising the following pharmaceutical composition: 0.01-2% ramelteinamide, 5-30% propylene glycol, 5-60% sulfobutyl ether-β-cyclodextrin, 0.01-1% EDTA·2Na, and 0.01-0.1% benzalkonium chloride. This patent does not disclose its brain targeting properties or nasal ciliary toxicity, and it has been verified that the nasal spray prepared with this formulation has poor atomization and cannot be sprayed smoothly.

[0007] Currently, there is a lack of a suitable ramelteamide formulation that can produce a qualified nasal spray that can both avoid the first-pass effect and improve the bioavailability of ramelteamide, as well as target brain tissue and make administration simple and convenient for patients. Summary of the Invention

[0008] The present invention primarily addresses the deficiency in existing technologies regarding the lack of suitable ramelteinamide nasal delivery formulations by providing a ramelteinamide-containing pharmaceutical composition and a nasal delivery formulation. This pharmaceutical composition can be used to prepare a suitable nasal delivery formulation, which, compared to oral tablets, improves the bioavailability of ramelteinamide and increases the drug concentration targeting brain tissue.

[0009] The present invention mainly solves the above-mentioned technical problems through the following technical solutions.

[0010] One aspect of the present invention provides a pharmaceutical composition containing ramelteamide, comprising ramelteamide and polyethylene glycol.

[0011] Another aspect of the present invention provides a pharmaceutical composition containing ramelteamide, comprising ramelteamide and a solubilizer, wherein the solubilizer is polyethylene glycol.

[0012] The researchers of this invention unexpectedly discovered that replacing propylene glycol, the solubilizer in the publicly disclosed ramelteamide nasal delivery formulation, with polyethylene glycol, which acts as an enzyme inhibitor or absorption enhancer in the prior art nasal delivery formulation, not only serves as a solubilizer, making ramelteamide dissolve clearly in water, but also overcomes the defect that the existing ramelteamide nasal delivery formulation cannot be properly atomized (i.e., sprayed as a mist from a nasal spray device).

[0013] In a specific embodiment of the present invention, the pharmaceutical composition is used for nasal administration, such as intranasal mucosal administration. The nasal administration of the pharmaceutical composition can be accomplished using a nasal spray device. The nasal spray device can be conventional in the art, generally comprising a reservoir and a spray pump. The reservoir stores the pharmaceutical composition, and the spray pump is, for example, a VP7 spray pump. The atomized particle size D50 of the pharmaceutical composition sprayed by the nasal spray device is 10-100 μm, preferably 40-50 μm, for example, 44.7 μm.

[0014] In this invention, the pharmaceutical composition can be used to prepare a drug for treating insomnia or relieving jet lag and related symptoms.

[0015] In specific embodiments of the present invention, the pharmaceutical composition is in liquid form, including but not limited to: solutions, suspensions, micelles, in-situ gels, nanocrystals, nanoemulsions, liposomes, inclusion complexes, or self-emulsifying drug delivery systems.

[0016] In a specific embodiment of the present invention, the pharmaceutical composition is an aqueous composition, meaning that the solvent in the pharmaceutical composition is mainly water, for example, 60% by weight of the pharmaceutical composition is water. The water content can be 65% by weight to 90% by weight, for example, 75% by weight, 80% by weight, 85% by weight, or 87% by weight, where the weight percentage refers to the percentage of the weight of the water to the total weight of the pharmaceutical composition.

[0017] In this invention, the osmotic pressure of the pharmaceutical composition can be 100-900 mosmol / kg, preferably 300-600 mosmol / kg, for example 348 mosmol / kg, 337 mosmol / kg, 548 mosmol / kg or 550 mosmol / kg.

[0018] In this invention, the pH value of the pharmaceutical composition is preferably 4.5-6.5, for example 5.5 or 6. In a specific embodiment of this invention, the pH value is adjusted by hydrochloric acid.

[0019] In this invention, the viscosity of the pharmaceutical composition is preferably 2-8 cP, for example 2.6 cP or 7.26 cP.

[0020] In this invention, the polyethylene glycol can be used as a solubilizer.

[0021] In this invention, the polyethylene glycol can be used as an osmotic pressure regulator.

[0022] In this invention, the polyethylene glycol is HO-(CH2CH2O). n -H, where n is the average number of oxyethylene groups, n is 4-14, preferably 8-10. In the art, the type of polyethylene glycol is usually expressed in the form of its average molecular weight. The average molecular weight of the polyethylene glycol used in this invention is preferably 200-600 g / mol, more preferably 350-450 g / mol, for example 400 g / mol. In a specific embodiment of this invention, polyethylene glycol 400 is used, i.e., polyethylene glycol with an average molecular weight of 400 g / mol. The average molecular weight can be understood in the conventional sense in the art, usually referring to weight-average molecular weight.

[0023] In this invention, the molar concentration of polyethylene glycol, based on 1L of the pharmaceutical composition, can be 2-750 mmol / L, preferably 100-500 mmol / L, such as 100 mmol / L, 125 mmol / L, 250 mmol / L or 300 mmol / L.

[0024] In this invention, the content of polyethylene glycol can be 0.1% to 30% by weight. In a preferred embodiment of this invention, the content of polyethylene glycol is 1-10% by weight, for example, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, or 9% by weight. Wherein, the percentage by weight is the percentage of the weight of the polyethylene glycol to the total weight of the pharmaceutical composition.

[0025] In this invention, the content of ramelteinamide can be selected according to the required dosage, and can be 0.01% to 10% by weight. In a preferred embodiment of this invention, the content of ramelteinamide is 0.1% to 1% by weight, for example, 0.4% by weight or 0.8% by weight. Wherein, the weight% is the percentage of the weight of ramelteinamide to the total weight of the pharmaceutical composition.

[0026] In a preferred embodiment of the present invention, the molar ratio of rameltein to polyethylene glycol is 1:(0.5-10), for example 1:0.6, 1:1.6, 1:4, 1:8 or 1:9.

[0027] In a specific embodiment of the present invention, the weight ratio of rameltein to polyethylene glycol is 1:(1-40), preferably 1:(1-25); for example, 1:1.25, 1:2.5, 1:6.25, 1:12.5 or 1:20.

[0028] As will be known to those skilled in the art from the description of this invention, the pharmaceutical composition described herein may contain appropriate amounts of propylene glycol or other polyols as solubilizers, for example, propylene glycol or other polyols at concentrations of 500 mmol / L or less, 400 mmol / L or less, 300 mmol / L or less, 200 mmol / L or less, 100 mmol / L or less, or 0 mmol / L. In a preferred embodiment of this invention, propylene glycol or other polyols are not present.

[0029] In this invention, the pharmaceutical composition may contain other osmotic pressure regulators. The content of these other osmotic pressure regulators is preferably less than 4.2% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or 0% by weight, where % by weight refers to the percentage of the weight of the other osmotic pressure regulator relative to the total weight of the pharmaceutical composition. These other osmotic pressure regulators include mannitol.

[0030] The term osmotic pressure regulator refers to an excipient that can adjust the osmotic pressure of a pharmaceutical composition to a certain extent, so that it is equal to or close to the osmotic pressure of the body fluids in the whole body and / or the administration site of the drug.

[0031] In this invention, the pharmaceutical composition further includes absorption enhancers conventional in the art. These absorption enhancers are commonly used excipients in the preparation of nasal drug delivery formulations, and they can improve nasal absorption and shorten the time to peak concentration. The absorption enhancers include, but are not limited to, surfactants and / or cyclodextrins and their derivatives.

[0032] The content of the absorption enhancer can be conventional in the art, typically 1-60% by weight, preferably 5-20% by weight, for example 10%, 12%, or 15% by weight, where the weight percentage refers to the percentage of the weight of the absorption enhancer to the total weight of the pharmaceutical composition.

[0033] The surfactants include one or more of Tween 80, Tween 20, Span 20, poloxamer 188, poloxamer 407, polyoxyethylene castor oil, polyethylene glycol-12-hydroxystearate, sucrose laurate, and alkyl glycosides.

[0034] The cyclodextrins and their derivatives may include β-cyclodextrins and their derivatives and / or γ-cyclodextrins and their derivatives. Preferably, the β-cyclodextrins and their derivatives include sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin.

[0035] In this invention, the pharmaceutical composition further includes a bioadhesive conventional in the art. The bioadhesive is a commonly used excipient in conventional nasal drug delivery formulations, which reduces drug clearance from the nasal mucosa and prolongs the contact time between the drug and the nasal mucosa. The bioadhesive may include one or more of dextran, sucrose, pectin, microcrystalline cellulose, sodium alginate, sodium hyaluronate, and chitosan. The bioadhesive contains less than 0.05% by weight, less than 0.01% by weight, or 0% by weight of nonionic etherified cellulose, such as hydroxypropyl methylcellulose. Sodium alginate is preferably the bioadhesive.

[0036] The content of the bioadhesive can be conventional in the art, and can be 0.01%-1% by weight, preferably 0.01-0.5% by weight, for example 0.1% by weight, where the weight% refers to the percentage of the weight of the bioadhesive to the total weight of the pharmaceutical composition.

[0037] In this invention, the pharmaceutical composition may further include stabilizers conventional in the art. The stabilizer may include disodium edetate.

[0038] The content of the stabilizer can be conventional in the art, and can be 0.01%-1% by weight, preferably 0.01-0.5% by weight, for example 0.1% by weight, where the weight% refers to the percentage of the weight of the stabilizer to the total weight of the pharmaceutical composition.

[0039] In this invention, the pharmaceutical composition may further include a conventional antimicrobial agent in the art, the addition of which can prevent the growth of microorganisms in the liquid formulation. The antimicrobial agent may include one or more of benzalkonium chloride, benzyl alcohol, phenethyl alcohol, potassium sorbate, and sodium benzoate.

[0040] The content of the antibacterial agent can be conventional in the art, and can be 0.01%-2% by weight, preferably 0.01%-1% by weight, for example 0.07% by weight or 0.5% by weight, where the % by weight refers to the percentage of the weight of the antibacterial agent to the total weight of the pharmaceutical composition.

[0041] In this invention, the pharmaceutical composition may further include enzyme inhibitors conventional in the art. These enzyme inhibitors are commonly used excipients in nasal administration formulations. The nasal cavity contains cytochrome P450 enzymes, which hinder drug adhesion and absorption; adding the enzyme inhibitors can enhance drug absorption. The enzyme inhibitors may include one or more of carmostat mesylate, cyclosporine A, rifampin, and polyethylene glycol. In specific embodiments of this invention, the enzyme inhibitors may not be added, and the polyethylene glycol may also act as an enzyme inhibitor.

[0042] In a specific embodiment of the present invention, the pharmaceutical composition comprises 0.1-1 wt% ramelteamide, 5-20 wt% sulfobutyl-β-cyclodextrin, 1-15 wt% polyethylene glycol 400, 0.01-1 wt% benzalkonium chloride, 0.01-1 wt% disodium edetate, and the balance being water. The pharmaceutical composition may be an inclusion complex solution. Preferably, the pharmaceutical composition comprises 0.1-1 wt% rameltein, 5-12 wt% sulfobutyl-β-cyclodextrin, 1-5 wt% polyethylene glycol 400, 0.01-1 wt% benzalkonium chloride, 0.01-1 wt% disodium edetate, and the balance being water; for example, it comprises 0.4 wt% rameltein, 12 wt% sulfobutyl-β-cyclodextrin, 5 wt% polyethylene glycol 400, 0.07 wt% benzalkonium chloride, 0.1 wt% disodium edetate, and the balance being water. The wt% refers to the percentage of each component by weight relative to the total weight of the pharmaceutical composition.

[0043] In a specific embodiment of the present invention, the pharmaceutical composition comprises 0.1-1 wt% ramelteamide, 5-15 wt% polyethylene glycol-12-hydroxystearate, 1-10 wt% polyethylene glycol 400, 0.1-1 wt% benzyl alcohol, 0.01-1 wt% disodium edetate, and the balance being water. The pharmaceutical composition may be a micellar solution. The wt% refers to the percentage of each component by weight relative to the total weight of the pharmaceutical composition.

[0044] In a specific embodiment of the present invention, the pharmaceutical composition comprises 0.1-1 wt% ramelteinamide, 5-15 wt% polyethylene glycol-12-hydroxystearate, 1-10 wt% polyethylene glycol 400, 0.1-1 wt% benzyl alcohol, 0.01-1 wt% sodium alginate, and the balance being water. This pharmaceutical composition may be an in-situ gel solution. The wt% refers to the percentage of each component's weight relative to the total weight of the pharmaceutical composition.

[0045] In this invention, the preparation method of the pharmaceutical composition can be conventional in the art, which is to mix the components evenly.

[0046] In a specific embodiment of the present invention, the preparation method includes: mixing the ramelteinamide with the polyethylene glycol, then mixing the mixture with other excipients, and optionally finally adding water to bring the total to 100% by weight. The solvent in the mixture of the other excipients is water.

[0047] The other excipients may be one or more of the absorption promoter, the stabilizer, the antibacterial agent, and the bioadhesive.

[0048] Another aspect of the present invention provides a nasal administration formulation comprising the pharmaceutical composition as described above.

[0049] In this invention, the nasal administration formulation can be conventional in the art, and is preferably a nasal spray.

[0050] In this invention, those skilled in the art will understand that the nasal delivery formulation typically includes a nasal delivery system. The nasal delivery system is preferably a nasal spray device comprising a reservoir and a spray pump. In a specific embodiment of this invention, the spray pump is a VP7.

[0051] Positive and progressive effects: The pharmaceutical composition of the present invention exhibits high stability and excellent atomization when prepared as a nasal delivery formulation, ensuring smooth dispensing. Compared to oral formulations, this formulation has higher relative bioavailability, faster onset of action, and higher drug concentrations targeting brain tissue. Attached Figure Description

[0052] Figure 1 shows the concentration-time curves of rameltetinamide in beagle dogs for the nasal spray formulations prepared from the pharmaceutical compositions of Examples 1-3 of the present invention.

[0053] Figure 2 shows the concentration-time curve of rametamide in rat brain tissue of the nasal spray formulation prepared by the pharmaceutical composition of Example 3 of the present invention. Detailed Implementation

[0054] To make the technical means, inventive features, achieved objectives, and effects of the invention readily understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the scope of the invention.

[0055] In this document, the term "micelle" refers to an ordered aggregate of molecules that begins to form in large quantities in an aqueous solution when the concentration of a surfactant reaches a certain level. In a micelle, the hydrophobic groups of the surfactant molecules aggregate to form the micelle core, while the hydrophilic polar groups form the micelle outer layer. In the art, the addition of polyethylene glycol-12-hydroxystearate to liquid pharmaceutical compositions commonly results in micelle formation.

[0056] In this article, the term "in situ gel" refers to a type of formulation that, after being administered in solution form, undergoes a phase transition immediately at the site of application, transforming from a liquid state to a non-chemically cross-linked semi-solid gel. In this field, the addition of sodium alginate to liquid pharmaceutical compositions typically results in an in situ gel form.

[0057] In this article, the term "inclusion complex" refers to a class of organic crystals. Their structure contains two structural units; that is, an inclusion complex is composed of two compounds: one is a compound that traps other compounds within the cavities of its structural framework, called the inclusion agent or host molecule; the other is a compound trapped within the cavities or channels of the inclusion agent's structure, called the included agent or guest molecule. Common compounds that can form cavities or channels include crown ethers and cyclodextrins. In this field, the addition of sulfobutyl-β-cyclodextrin to liquid pharmaceutical compositions typically forms inclusion complexes.

[0058] In this article, the term "nasal spray formulation" refers to a dosage form that achieves a therapeutic effect by instilling a fine mist containing the active pharmaceutical ingredient into the nasal cavity through the action of a spray pump.

[0059] In this invention, room temperature generally refers to 15-25℃.

[0060] The viscosity testing methods for the following embodiments and comparative examples are as follows: using the rotational viscometer, a Brookfield DV2T rotational viscometer (AMETEK, USA), a rotor of size 61, 100 ml of the solution to be tested was poured into the test cup for viscosity testing, the test rotation speed was 150 rpm / min, and the test time was 2 min.

[0061] The following examples and comparative examples illustrate the osmotic pressure testing methods: The osmotic pressure of the formulation is measured using an osmometer. 0.05 mL of the test solution is added to an EP tube, and the osmotic pressure value is measured.

[0062] Example 1 Rametamide micelles

[0063] According to the formulation shown in Table 1 below, ramelteinamide was dissolved in polyethylene glycol 400 (PEG-400) at 40°C to obtain solution 1. Polyethylene glycol-12-hydroxystearate, benzyl alcohol, and disodium edetate were dissolved in 70% by weight purified water at room temperature to obtain solution 2. Solutions 1 and 2 were mixed and the pH of the mixture was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining ramelteinamide micelles.

[0064] Table 1

[0065] The micelle solution prepared using the above formula and process was clarified and tested to have a viscosity of 2.6 cP, an osmotic pressure of 348 mosmol / kg, and an average particle size D50 of 13.07 nm before being loaded into the nasal spray device.

[0066] Example 2: Rametamide in situ gel

[0067] According to the formulation shown in Table 2 below, ramelteinamide was dissolved in PEG-400 at 40°C to obtain solution 1. Polyethylene glycol-12-hydroxystearate, benzyl alcohol, and sodium alginate were dissolved in 70% (w / w) purified water at room temperature to obtain solution 2. After mixing solutions 1 and 2, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining ramelteinamide in situ gel.

[0068] Table 2

[0069] The in-situ gel solution prepared using the above formula and process was clarified and tested to have a viscosity of 7.26 cP, an osmotic pressure of 337 mosmol / kg, and an average particle size D50 of 13 nm before being loaded into the spray device.

[0070] Example 3 Rametamide Inclusion Complex

[0071] According to the formulation shown in Table 3 below, rameltein was dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C (solution 2 was kept at 60°C during the mixing process), and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the rameltein inclusion complex.

[0072] Table 3

[0073] The inclusion complex solution prepared using the above formula and process was clarified and tested to have a viscosity of 2.0 cP, an osmotic pressure of 548 mosmol / kg, and a pH of 5.5. The atomized particle size D50 of this true solution after being loaded into a nasal spray device (VP7, 50 μL, screw cap) was 44.7 μm.

[0074] Example 4 Rametamide Inclusion Complex

[0075] According to the formulation shown in Table 4 below, rameltein was dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C (solution 2 was kept at 60°C during the mixing process), and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the rameltein inclusion complex.

[0076] Table 4

[0077] The inclusion complex solution prepared using the above formula and process was clarified, and its osmotic pressure was tested to be 340 mosmol / kg. When this inclusion complex solution was administered into a nasal spray device (VP7, 50 μL, screw cap), the drug was well atomized into small droplets by the nasal spray device, and the spray pattern was conical, indicating good atomization effect.

[0078] Example 5 Rametamide Inclusion Complex

[0079] According to the formulation shown in Table 5 below, rameltein was dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C, and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the rameltein inclusion complex.

[0080] Table 5

[0081] The solution prepared using the above formula and process was clear, and after testing, the osmotic pressure was 1404 mosmol / kg. The solution could be atomized and sprayed out normally.

[0082] Example 6 Rametamide Inclusion Complex

[0083] According to the formulation shown in Table 6 below, rameltein was dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C, and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the rameltein inclusion complex.

[0084] Table 6

[0085] The solution prepared using the above formula and process was clear and tested to have an osmotic pressure of 946 mosmol / kg. The solution could be well atomized into small droplets by the nasal spray device, and the spray pattern was conical.

[0086] Example 7 Rametamide Inclusion Complex

[0087] According to the formulation shown in Table 7 below, rameltein was dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C, and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the rameltein inclusion complex.

[0088] Table 7

[0089] The solution prepared using the above formula and process was clear, and after testing, the osmotic pressure was 790 mosmol / kg. The solution could be atomized and sprayed out normally.

[0090] Example 8 Rametamide Inclusion Complex

[0091] The prescription is shown in Table 8 below. Ramelteamide was dissolved in PEG-400 at room temperature to obtain solution 1. Sulfobutyl-β-cyclodextrin, mannitol, benzalkonium chloride, and disodium edetate were dissolved in purified water to obtain solution 2. Solution 1 was added to solution 2 at 60°C, and after stirring and mixing, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water was added to dilute and bring the volume to 100%, thus obtaining the ramelteamide inclusion complex.

[0092] Table 8

[0093] The solution prepared using the above formula and process was clear and tested to have an osmotic pressure of 992 mosmol / kg. The solution could be well atomized into small droplets by the nasal spray device, and the spray pattern was conical.

[0094] Comparative Example 1: Rametamide Inclusion Complex

[0095] The prescription is shown in Table 9 below. Completely dissolve rameltein in propylene glycol, then gradually add this solution to a sulfobutyl-β-cyclodextrin solution containing disodium edetate and benzalkonium chloride. Finally, add purified water to a final volume of 1 L.

[0096] Table 9

[0097] The solution prepared using the above formula and process was clarified. After testing, the viscosity was 2.8 cP, the osmotic pressure (diluted 10 times) was 277 mosmol / kg, the atomization effect was poor, the size of the sprayed droplets was uneven, the spray distance of the liquid was significantly longer, the ellipticity of the spray was narrower, and it could not be sprayed normally.

[0098] Comparative Example 2: Rametamide Inclusion Complex

[0099] The prescription is shown in Table 10 below. Rametamide is dissolved in PEG-400 at room temperature to obtain solution 1. HPMC is dissolved in purified water. Sulfobutyl-β-cyclodextrin, benzalkonium chloride, and disodium edetate are added to the HPMC solution and dissolved to obtain solution 2. Solution 1 is added to solution 2 at 60°C, and after stirring and mixing, the pH of the mixed solution is adjusted to 5.0 with hydrochloric acid. Finally, an appropriate amount of purified water is added to dilute and bring the volume to 100%.

[0100] Table 10

[0101] When the solution was loaded into the nasal spray device (VP7, 50μL, screw cap), the atomization effect was poor, and the spray appeared as a water column.

[0102] Effect Example 1 Stability

[0103] The impurity content in Examples 1-3 was determined using HPLC. The impurities included compounds I and II as shown below:

[0104] The HPLC detection method is as follows:

[0105] Column: Waters Atlantis T3 (250x4.6mm, 5 μm) or equivalent column;

[0106] Ghost peak capture column: Welch Ghost-Buster, 4.6x50mm;

[0107] Column temperature: 25℃; flow rate: 1.2mL / min; detection wavelength: 220nm; injection volume: 25µL; mobile phase: mobile phase A is 0.1% phosphoric acid solution, mobile phase B is acetonitrile-methanol (6:4), gradient elution is performed according to Table 11.

[0108] Table 11

[0109] (1) Stability of ramelteamide micelle formulation

[0110] The micelle solution obtained in Example 1 was loaded into a nasal spray device (VP7, 50 μL, screw cap). The impurity content of the solution after being sprayed by the nasal spray device was detected by the above-mentioned HPLC detection method after 0 days and after being placed at high temperature for 10 days. At the same time, the properties of the solution were observed by the naked eye under natural light. The results are shown in Table 12 below.

[0111] Table 12

[0112] (2) Stability of ramelteamide in situ gel formulation

[0113] The in-situ gel obtained in Example 2 was loaded into a nasal spray device (VP7, 50 μL, screw cap). The impurity content of the solution after being sprayed by the nasal spray device was detected by the above-mentioned HPLC detection method after 0 days and 10 days of high temperature. At the same time, the properties of the solution were observed by the naked eye under natural light. The results are shown in Table 13 below.

[0114] Table 13

[0115] (3) Stability of rameltein inclusion complex formulations

[0116] The cyclodextrin inclusion complex obtained in Example 3 was loaded into a nasal spray device (VP7, 50 μL, screw cap). The impurity content of the solution after spraying through the nasal spray device was detected at 0 days, 1 month, and 3 months using the HPLC method described above. The results are shown in Table 14 below. Meanwhile, in all experiments, the solution was observed to be colorless and transparent under natural light.

[0117] Table 14

[0118] Note: Acceleration conditions are 40℃ / 75%RH; long-term conditions are 25℃ / 60%RH. 1M and 3M refer to 1 month and 3 months, respectively.

[0119] Example 2: Pharmacokinetic Study of Beagle Dogs

[0120] The solutions obtained in Examples 1-3 were respectively loaded into nasal spray devices (VP7, 50 μL, screw cap) to obtain 3 groups of nasal spray formulations, which were named micelle formulation, in situ gel formulation and inclusion complex formulation, respectively. The pharmacokinetics of each nasal spray formulation in beagle dogs were tested.

[0121] Male beagles were weighed before the experiment and randomly divided into four groups: tablet group, micelle formulation group, in-situ gel formulation group, and inclusion complex formulation group, with three dogs in each group. The beagles were fasted overnight the day before administration. The tablet group received 8 mg ramelteamide tablets orally. The remaining three groups were administered 0.4 mg (0.2 mg / spray, one spray on each side) of the micelle formulation, in situ gel formulation, and inclusion complex formulation via nasal spray into the nasal cavity, respectively. Venous blood was collected from the limbs at time points of 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, and 4 h after administration and placed in labeled EDTA-K2 anticoagulant tubes. Plasma was separated by centrifugation within one hour of blood collection at 4°C, 5000 g, and 6 min. The separated plasma was placed in labeled EP tubes for LC-MS / MS analysis to determine the blood concentration of ramelteinamide. Figure 1 shows the concentration-time curves of ramelteinamide for each nasal spray formulation in beagle dogs. Pharmacokinetic parameters were calculated using WinNonlin software, and the results are shown in Table 15 below.

[0122] Table 15

[0123] Note: T 1 / 2 This refers to the time required for the drug's peak concentration in plasma to decrease by half; T max Time to reach peak plasma concentration; C maxThe highest plasma concentration; AUC is the area under the plasma concentration-time curve; AUC 0-t The area under the curve (AUC) refers to the time point from the start of drug administration to the last measurable blood drug concentration. 0-inf "Indicates the AUC value from the start of drug administration to indefinite time; nasal spray refers to the administration of drugs into the nasal cavity using a nasal spray formulation."

[0124] As can be seen from the PK results in Table 15, compared with oral tablets (T... max Compared to 0.25h, the T values ​​of micelle formulations, in-situ gel formulations, and inclusion complex formulations administered via nasal spray were significantly lower. max The onset times were 0.167 h (10.02 min), 0.083 h (4.98 min), and 0.167 h (10.02 min), respectively, indicating faster onset of action. Compared to oral tablets, the relative bioavailability of the micelle formulation, in-situ gel formulation, and inclusion complex group administered via nasal spray were 287%, 228%, and 189%, respectively, all showing significant improvements.

[0125] Example 3: Study on nasal ciliary toxicity and distribution in rat brain tissue

[0126] Nasal ciliary toxicity: 0.5 mL of the micelle liquid prepared in Example 1 and the inclusion complex liquid prepared in Example 3 were respectively pipetted and added to the palatine of two toads. After 30 min, the palatine mucosa was peeled off and slides were prepared for observation under a microscope. Using physiological saline as a control group, the percentage of ciliary movement time was calculated (i.e., the time required from the start of administration to the complete cessation of ciliary movement was recorded; the control group was 100%, and the relative percentage of the experimental group was calculated). The ciliary sustained movement time ratio of the rameltein amide inclusion complex in Example 3 was 90.3%, indicating almost no ciliary toxicity. The ciliary sustained movement time ratio of the rameltein amide micelles in Example 1 was 54.6%, also indicating a low level of ciliary toxicity.

[0127] Distribution in rat brain tissue: The ramelteinamide inclusion complex prepared in Example 3 was packaged into a nasal spray device (VP7, 50 μL, screw cap) to prepare a nasal spray formulation. The distribution in plasma and brain tissue of SD rats after nasal administration was studied using this nasal spray formulation. After euthanasia with CO2, plasma, cerebrospinal fluid, olfactory bulb, and thalamus were collected at 5 min, 15 min, 30 min, 45 min, and 60 min after nasal administration. All samples were transferred to centrifuge tubes and immediately stored on moist ice in the dark for 1 hour, followed by LC-MS / MS analysis. Figure 2 shows the ramelteinamide concentration-time curve in rat brain tissue. The experimental results are shown in Table 16 below.

[0128] Table 16

[0129] Table 16 shows that after nasal spray administration, the drug pharmacokinetic (PK) levels in plasma and thalamus were essentially the same, indicating that the drug composition of Example 3 can cross the blood-brain barrier and reach brain tissue. Referring to publicly available information on commercially available tablet products, when the rat dosage is 1 mg / kg, the Cp of the plasma drug concentration after oral administration is... max The concentration was 17.5 ng / mL, and the AUC was... 0-t The plasma drug concentration is 1278 ng / mL*min, which is 4–10 times higher than that in brain tissue. The brain tissue concentration after oral administration can be calculated. max The concentration ranged from 1.75 to 4.38 ng / mL. The drug concentration in brain tissue of the nasal spray group was 28.7 to 71.9 times that of the orally administered brain tissue, indicating that the drug concentration in the targeted brain tissue after administration of the nasal spray formulation of this invention to the nasal cavity is much higher than that after oral administration.

[0130] Example 4: Pharmacokinetic Study of Crab-Eating Monkeys

[0131] Using common cynomolgus monkeys as research subjects, the rameltetinamide inclusion complex of Example 3 was administered intranasally via a nasal spray device (VP7, 50 μL, screw-type). Oral tablets were administered via gavage as a control. Blood samples were collected from the limb veins at predetermined time points for pharmacokinetic analysis. The monkeys were divided into four groups: low-dose group (0.2 mg / monkey), medium-dose group (0.4 mg / monkey), high-dose group (0.8 mg / monkey), and tablet group (8 mg / monkey). Blood sample processing: After removal from the monkey, samples were stored on crushed ice and centrifuged within 1 hour. Centrifugation conditions: 3500 rpm, 2220 x g, 15 min, 4℃. The supernatant was collected after centrifugation and analyzed. The results are shown in Table 17 below.

[0132] Table 17

[0133] In cynomolgus monkeys, plasma concentrations and exposure to rameltein increased with increasing dose. Compared to oral tablets, the relative bioavailability of rameltein inclusion complexes at different doses ranged from 373% to 482%, all showing significant improvements.

[0134] Based on the reference rat dosage of 1 mg / kg, the plasma drug concentration after oral administration is 4–10 times that in brain tissue. Therefore, when the dosage in cynomolgus monkeys is 8 mg / monkey, the drug concentration in brain tissue (thalamus) after oral administration is 5.88–50 ng / mL. The above rat brain tissue distribution results show that the drug pharmacokinetic (PK) levels in plasma and thalamus are basically consistent after nasal spray administration. This indicates that the drug PK levels in plasma and thalamus are consistent after nasal spray administration (0.4 mg / monkey), suggesting that the drug concentration in brain tissue after nasal spray administration is approximately 58.45 ng / mL, which is 23.4–198.8 times that after oral administration. Therefore, compared to oral administration, the targeted brain tissue drug concentration after nasal administration of this invention is higher.

[0135] In summary, the nasal spray formulation prepared using the pharmaceutical composition of the present invention not only overcomes the solubility defect of ramelteamide, but also solves the problem of the nasal spray formulation being difficult to atomize and spray smoothly. In preferred embodiments 1-4, the osmotic pressure can be kept below 600 mosmol / kg without the addition of additional osmotic pressure regulators, thus avoiding damage to the nasal cavity.

[0136] Further studies investigated the pharmacokinetics, ciliary toxicity, and brain targeting of the nasal spray formulation, all of which showed excellent efficacy to varying degrees. Experimental verification confirmed that the formulation's onset time is approximately 5-10 minutes, and the To of the in-situ gel... max With an onset time of only 4.98 minutes, it is faster than various existing ramelteamide formulations. Its bioavailability fully leverages the advantages of nasal spray formulations, achieving a relative bioavailability of 180%-300% compared to oral formulations. Ciliary toxicity is also low, especially in nasal spray formulations containing cyclodextrin derivatives, where the ciliary motility duration ratio is 90.3%, far exceeding the conventional standard (a higher ciliary motility duration ratio indicates lower toxicity to nasal cilia). High drug concentrations are achieved targeting brain tissue; rat brain tissue distribution results show that the drug concentration in the nasal spray group is 30-70 times higher than that in the brain tissue of the oral tablets. Pharmacokinetic results in cynomolgus monkeys also indicate that, compared to oral tablets, the relative bioavailability of nasal sprays at different doses can reach 350%-500%, and the drug concentration targeting brain tissue after nasal administration is 20-200 times higher than that after oral administration. Furthermore, the high relative bioavailability in beagle pharmacokinetic experiments and the significantly higher drug concentration in rat brain tissue experiments compared to oral administration indirectly demonstrate the drug's low membrane permeability and clearance effect through nasal mucociliary tracts.

[0137] As can be seen above, prior to obtaining the solution of this invention, some experiments were conducted according to existing technologies, but none of them yielded a qualified nasal spray device. For example, in Comparative Example 1, propylene glycol was used as a solubilizer, resulting in excessively high osmotic pressure and failure to spray normally; while adding HPMC resulted in a water column spray. However, when polyethylene glycol was chosen as an excipient in the preparation of nasal spray formulations, not only was the solution highly stable, but the aqueous drug composition could also be atomized and sprayed smoothly in the nasal spray device. Moreover, polyethylene glycol's contribution to osmotic pressure was very small, which may be related to the molar concentration of the substance. Theoretically, when the molecular weight of polyethylene glycol is 400 and the addition amount is 5 (wt%), the molar concentration = 50 g / L / 400 (g / mol) = 125 mmol / L. PEG cannot ionize in water, therefore the osmotic pressure of the solution is 125 mosmol / kg. Propylene glycol has a molecular weight of 76, an addition amount of 15 (volume%), and a density of 1.0381 g / cm³. 3The molar concentration is calculated as 150 g / L × 1.0381 / 76 (g / mol) = 2049 mmol / L. Propylene glycol cannot ionize in water, therefore the osmotic pressure of the solution is 2049 mosmol / kg. Experiments have verified that the osmotic pressure of a 5% (w / w) PEG-400 aqueous solution is 148 mosmol / kg, and the osmotic pressure of a 15% (v / v) propylene glycol aqueous solution diluted 1-fold is 1160 mosmol / kg, which is close to the theoretical calculation.

[0138] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A pharmaceutical composition containing ramelteinamide, characterized in that, It includes ramelteamide and polyethylene glycol.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is for nasal administration, such as intranasal mucosal administration; And / or, the pharmaceutical composition is a medicine for preparing a treatment for insomnia or a remedy for jet lag; And / or, the pharmaceutical composition is in liquid form, such as micelles, in situ gels, or inclusion complexes; And / or, the pharmaceutical composition is an aqueous composition; the water content in the aqueous composition is preferably 65-90% by weight, more preferably 80-85% by weight; And / or, the osmotic pressure of the pharmaceutical composition is 100-900 mosmol / kg, preferably 300-600 mosmol / kg, for example 348 mosmol / kg, 337 mosmol / kg, 548 mosmol / kg or 550 mosmol / kg; And / or, the pH value of the pharmaceutical composition is 4.5-6.5, for example 5.5 or 6; And / or, the viscosity of the pharmaceutical composition is 2-8 cP, for example 2.6 cP or 7.26 cP.

3. The pharmaceutical composition according to claim 1, characterized in that, The average molecular weight of the polyethylene glycol is 200-600 g / mol, preferably 350-450 g / mol, for example 400 g / mol; And / or, based on 1L of the pharmaceutical composition, the molar concentration of the polyethylene glycol is 2-750 mmol / L, for example 100 mmol / L, 125 mmol / L, 250 mmol / L or 300 mmol / L; And / or, the content of the polyethylene glycol is 0.1% to 30% by weight, preferably 1% to 10% by weight, for example 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight or 9% by weight, wherein the weight% refers to the percentage of the weight of the polyethylene glycol to the total weight of the pharmaceutical composition; And / or, the content of rameltein is 0.01%-10% by weight, preferably 0.1%-1% by weight, for example 0.4% or 0.8% by weight, wherein the percentage by weight refers to the percentage of the weight of rameltein to the total weight of the pharmaceutical composition; And / or, the molar ratio of rameltein to polyethylene glycol is 1:(0.5-10), for example 1:0.6, 1:1.6, 1:4, 1:8 or 1:9; And / or, the weight ratio of the rameltein to the polyethylene glycol is 1:(1-40), for example 1:1.25, 1:2.5, 1:6.25, 1:12.5 or 1:20; And / or, the pharmaceutical composition contains less than 4.2% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or 0% by weight of mannitol; And / or, based on 1L of the pharmaceutical composition, the pharmaceutical composition contains propylene glycol at concentrations of 500 mmol / L or less, 400 mmol / L or less, 300 mmol / L or less, 200 mmol / L or less, 100 mmol / L or less, or 0 mmol / L.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical composition further includes an absorption enhancer; the absorption enhancer includes surfactants and / or cyclodextrins and their derivatives; The surfactant is preferably polyethylene glycol-12-hydroxystearate; The cyclodextrin and its derivatives are preferably β-cyclodextrin and its derivatives and / or γ-cyclodextrin and its derivatives; wherein the β-cyclodextrin and its derivatives preferably include sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin. The content of the absorption enhancer is preferably 1-60% by weight, more preferably 5-20% by weight, for example 10% by weight, 12% by weight or 15% by weight, where the weight% refers to the percentage of the weight of the absorption enhancer to the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition further includes a bioadhesive; the bioadhesive preferably includes one or more of dextran, sucrose, pectin, microcrystalline cellulose, sodium alginate, sodium hyaluronate, and chitosan; the bioadhesive preferably contains less than 0.05% by weight, less than 0.01% by weight, or 0% by weight of nonionic etherified cellulose, such as hydroxypropyl methylcellulose; the bioadhesive is preferably sodium alginate. The content of the bioadhesive is preferably 0.01%-1% by weight, more preferably 0.01%-0.5% by weight, for example 0.1% by weight, where the % by weight refers to the percentage of the weight of the bioadhesive to the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition further includes a stabilizer; the stabilizer preferably includes disodium edetate. The stabilizer content is preferably 0.01%-1% by weight, more preferably 0.01%-0.5% by weight, for example 0.1% by weight, where the weight% refers to the percentage of the stabilizer's weight to the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition further includes an antibacterial agent; the antibacterial agent preferably includes one or more of benzalkonium chloride, benzyl alcohol, phenethyl alcohol, potassium sorbate, and sodium benzoate; The content of the antibacterial agent is preferably 0.01%-2% by weight, more preferably 0.01%-1% by weight, for example 0.07% by weight or 0.5% by weight, where the % by weight refers to the percentage of the weight of the antibacterial agent to the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition comprises 0.1-1% by weight of rameltein, 5-20% by weight of sulfobutyl-β-cyclodextrin, 1-15% by weight of polyethylene glycol 400, 0.01-1% by weight of benzalkonium chloride, 0.01-1% by weight of disodium edetate, and the balance being water, wherein the weight% refers to the percentage of the weight of each component relative to the total weight of the pharmaceutical composition; Preferably, the pharmaceutical composition comprises 0.1-1 wt% rameltein, 5-12 wt% sulfobutyl-β-cyclodextrin, 1-5 wt% polyethylene glycol 400, 0.01-1 wt% benzalkonium chloride, 0.01-1 wt% disodium edetate, and the balance being water; for example, it comprises 0.4 wt% rameltein, 12 wt% sulfobutyl-β-cyclodextrin, 5 wt% polyethylene glycol 400, 0.07 wt% benzalkonium chloride, 0.1 wt% disodium edetate, and the balance being water.

9. The pharmaceutical composition according to any one of claims 1-8, characterized in that, The preparation method of the pharmaceutical composition includes the following steps: after mixing the ramelteinamide and the polyethylene glycol, the mixture is then mixed with a mixture of other excipients, and optionally, water is added to bring the final weight to 100% by weight; wherein, the other excipients preferably include one or more of the absorption promoter, the stabilizer, the antibacterial agent and the bioadhesive.

10. A nasal delivery formulation, characterized in that, It comprises the pharmaceutical composition as described in any one of claims 1-9; The nasal administration preparation may be a nasal spray; the spray pump in the nasal spray preparation is preferably a VP7.

Images