Pharmaceutical composition containing ramelteon and nasal delivery preparation

Abstract

The invention relates to a pharmaceutical composition containing ramelteon and a nasal delivery preparation. The pharmaceutical composition comprises ramelteon and polyethylene glycol. The pharmaceutical composition disclosed by the invention is high in stability, can be used for preparing a pharmaceutical preparation meeting the quality requirement of a nasal delivery preparation, and can be used for improving the bioavailability of ramelteon and the drug concentration of targeted brain tissues compared with oral tablets.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition containing ramelteon and a nasal administration preparation. BACKGROUND

[0002] The overall prevalence of insomnia in China is 15.0%. Long-term insomnia affects the normal life and work of individuals and increases the risk of various health problems. Severe sleep loss can reduce the work efficiency and alertness level of patients, and even may cause serious accidents, causing huge losses. The main intervention methods for insomnia include drug treatment, psychological treatment, physical treatment and Chinese traditional medicine treatment, etc.

[0003] The 2017 Chinese insomnia diagnosis and treatment guidelines recommend the first choice of melatonin receptor agonists (such as ramelteon). Ramelteon can selectively stimulate the melatonin type 1 receptor (MT1) and type 2 receptor (MT2) in the brain, increase slow wave sleep (SWS) and rapid eye movement sleep (REW), and is used for the treatment of insomnia with difficulty falling asleep as the main complaint and insomnia caused by circadian rhythm disorders. The incidence of ramelteon side effects is low, and it is the first non-addictive insomnia treatment drug not listed as a special control. Since there is no drug dependence, it will not produce withdrawal symptoms, so it has been approved for long-term treatment of insomnia.

[0004] Ramelteon has very high MT1 / MT2 receptor agonist activity in vitro (EC50<1nM), but due to its short half-life [JClin Sleep Med 3(5):495-504], the amount of distribution in the brain is very small, which affects the full play of its pharmacodynamic effect. The current marketed product of ramelteon is a tablet developed by Japan Takeda Pharmaceutical Company, with the trade name "ROZEREM". But the drug shows a strong first-pass effect after oral administration, and the absolute bioavailability is only 1.8%. Chinese invention patent CN104224741B discloses a preparation method of a conventional tablet, which improves the dissolution rate and stability of ramelteon by micronization treatment and addition of an antioxidant. CN113274365A provides a ramelteon immediate-release and sustained-release dual-release preparation, which quickly exerts a pharmacological effect and prolongs the action time of the drug. The two preparation methods are both oral administration, and the drug is basically absorbed in the digestive tract, which has a first-pass effect. CN112190555B discloses a preparation method of ramelteon sublingual tablets, which can avoid the liver first-pass effect and improve the bioavailability. However, the brain target concentration is not studied in the present application, and sublingual administration requires the patient to correctly place the drug under the tongue, which has high operation requirements.

[0005] Nasal preparations have the clinical advantages of rapid absorption, high bioavailability, avoidance of liver first-pass effect, and high patient compliance. Nasal preparations can bypass the blood-brain barrier through the olfactory nerve or the trigeminal nerve branch to achieve direct central nervous system administration, providing a relatively safer, more effective and convenient administration route for the treatment of brain or central nervous system diseases. However, the existing technology mainly studies tablets or sublingual administration of ramelteon, and rarely studies nasal sprays. This is likely because the nasal spray has higher requirements for the properties of the drug, which needs to be smoothly sprayed from the nasal spray device, and the poor water solubility of ramelteon makes the preparation of the nasal spray more difficult. This also shows that the nasal administration preparation has different regulations compared with oral and sublingual administration.

[0006] CN110996938A discloses a nasal spray or a nasal drop for intranasal administration, or a sublingual spray or a solid preparation for sublingual administration, which specifically comprises the following components: 0.01-2% of ramelteon, 5-30% of propylene glycol, 5-60% of sulfobutyl ether-beta cyclodextrin, 0.01-1% of EDTA.2Na and 0.01-0.1% of benzalkonium chloride. The patent does not disclose how the brain targeting and nasal cilia toxicity are, and the prepared nasal spray has poor atomization effect and cannot be smoothly sprayed.

[0007] At present, there is still a lack of a suitable ramelteon formulation to prepare qualified nasal spray preparations, which can not only avoid the first-pass effect to improve the bioavailability of ramelteon, but also target brain tissue and be easy for patients to operate. SUMMARY

[0008] The present application mainly aims to solve the defects of the prior art that there is a lack of qualified ramelteon nasal administration preparation formulation, and provides a pharmaceutical composition containing ramelteon and a nasal administration preparation. The pharmaceutical composition can prepare a qualified nasal administration preparation, which can improve the bioavailability of ramelteon and increase the drug concentration in the target brain tissue compared with oral tablets.

[0009] The present application mainly solves the above technical problems through the following technical solutions.

[0010] One aspect of the present application provides a pharmaceutical composition containing ramelteon, which comprises ramelteon and polyethylene glycol.

[0011] Another aspect of the present application provides a pharmaceutical composition containing ramelteon, which comprises ramelteon and a solubilizing agent, and the solubilizing agent is polyethylene glycol.

[0012] The inventors of the present application surprisingly found that the polyethylene glycol as an enzyme inhibitor or absorption enhancer in the prior art nasal administration preparation is replaced with the solubilizer propylene glycol in the prior art remimazane nasal administration preparation, which not only plays the role of solubilizer to make remimazane dissolve clearly in water, but also overcomes the defect that the existing remimazane nasal administration preparation cannot be properly atomized (i.e. sprayed from a nasal spray device as mist).

[0013] In specific embodiments of the present application, the pharmaceutical composition is for nasal administration, for example, intranasal mucosal administration. The pharmaceutical composition can be completed by a nasal spray device for the nasal administration. The nasal spray device can be conventional in the art, which generally includes a drug storage tank for storing the pharmaceutical composition and a spray pump, for example, a VP7 spray pump. Wherein, the atomization 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 the present application, the pharmaceutical composition can be used for preparing a drug for treating insomnia or relieving jet lag syndrome and related symptoms.

[0015] In specific embodiments of the present application, the pharmaceutical composition is in liquid form, including but not limited to: solution, suspension, micelle, in-situ gel, nanocrystal, nanoemulsion, liposome, clathrate or self-emulsifying drug delivery system.

[0016] In specific embodiments of the present application, the pharmaceutical composition is an aqueous composition, i.e. the solvent in the pharmaceutical composition is mainly water, for example, 60% by weight of the composition is water. The content of water can be 65%-90% by weight, for example, 75% by weight, 80% by weight, 85% by weight or 87% by weight, wherein the % by weight refers to the percentage of the weight of water in the total weight of the pharmaceutical composition.

[0017] In the present application, 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 the present application, the pH value of the pharmaceutical composition is preferably 4.5-6.5, for example, 5.5 or 6. In specific embodiments of the present application, the pH value is adjusted by hydrochloric acid.

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

[0020] In the present application, 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] The pharmaceutical composition of the present application can contain a suitable amount of propylene glycol or other polyols as a solubilizer, for example, can contain 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 of propylene glycol or other polyols, according to the description of the present application. In the preferred embodiments of the present application, no propylene glycol or other polyols are contained.

[0029] In the present application, the pharmaceutical composition can contain other osmotic pressure regulators. The content of the other osmotic pressure regulators is preferably less than 4.2 wt%, 3 wt% or less, 2 wt% or less, 1 wt% or less, or 0 wt%, wherein the wt% refers to the weight percentage of the other osmotic pressure regulator in the total weight of the pharmaceutical composition. The other osmotic pressure regulator includes mannitol.

[0030] The term osmotic pressure regulator refers to an auxiliary material that can adjust the osmotic pressure of the pharmaceutical composition to a certain extent, so as to be equal to or close to the osmotic pressure of the body fluid of the whole body and / or the local administration site of the subject.

[0031] In the present application, the pharmaceutical composition further comprises an absorption enhancer in the art. The absorption enhancer is an auxiliary material commonly used in the preparation of nasal administration preparations, which can improve the nasal absorption of drugs and shorten the peak time. The absorption enhancer includes but is not limited to a surfactant and / or a cyclodextrin and its derivative.

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

[0033] The surfactant includes 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 glycoside.

[0034] The cyclodextrin and its derivative can include β-cyclodextrin and its derivative and / or γ-cyclodextrin and its derivative. The β-cyclodextrin and its derivative preferably includes sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin.

[0035] In the present application, the pharmaceutical composition further comprises a bioadhesive agent which is conventional in the art. The bioadhesive agent is a common excipient for a nasal administration preparation in the art, and the bioadhesive agent can reduce the clearance of the drug by the nasal mucosa and prolong the contact time of the drug with the nasal mucosa. The bioadhesive agent can comprise one or more of dextran, sucrose, pectin, microcrystalline cellulose, sodium alginate, sodium hyaluronate, and chitosan. The bioadhesive agent contains 0.05% or less, 0.01% or less, or 0% of a non-ionic etherified cellulose such as hydroxypropyl methylcellulose. The bioadhesive agent is preferably sodium alginate.

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

[0037] In the present application, the pharmaceutical composition can further comprise a stabilizer which is conventional in the art. The stabilizer can comprise edetate disodium.

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

[0039] In the present application, the pharmaceutical composition can further comprise a bacteriostatic agent which is conventional in the art, and the addition of the bacteriostatic agent can prevent the growth of microorganisms in a liquid preparation. The bacteriostatic agent can comprise one or more of benzalkonium chloride, benzyl alcohol, phenyl ethanol, potassium sorbate, and sodium benzoate.

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

[0041] In the present application, the pharmaceutical composition can further comprise an enzyme inhibitor which is conventional in the art. The enzyme inhibitor is a common excipient for a nasal administration preparation, and cytochrome P450 enzymes and the like exist in the nasal cavity, which hinders the adhesion and absorption of the drug, and the addition of the enzyme inhibitor can enhance the absorption of the drug. The enzyme inhibitor can comprise one or more of carmofur mesylate, cyclosporin A, rifampicin, and polyethylene glycol. The enzyme inhibitor can not be added in the specific embodiments of the present application, and the polyethylene glycol can also function as the enzyme inhibitor.

[0042] In an embodiment of the present application, the pharmaceutical composition comprises 0.1-1 wt% ramelteon, 5-20 wt% sulfobutyl-β-cyclodextrin, 1-15 wt% polyethylene glycol 400, 0.01-1 wt% benzalkonium chloride, 0.01-1 wt% edetate disodium and the balance water. The pharmaceutical composition can be a clathrate solution. Preferably, the pharmaceutical composition consists of 0.1-1 wt% ramelteon, 5-12 wt% sulfobutyl-β-cyclodextrin, 1-5 wt% polyethylene glycol 400, 0.01-1 wt% benzalkonium chloride, 0.01-1 wt% edetate disodium and the balance water; for example, consists of 0.4 wt% ramelteon, 12 wt% sulfobutyl-β-cyclodextrin, 5 wt% polyethylene glycol 400, 0.07 wt% benzalkonium chloride, 0.1 wt% edetate disodium and the balance water. The wt% means the weight percentage of each component in the total weight of the pharmaceutical composition.

[0043] In an embodiment of the present application, the pharmaceutical composition comprises 0.1-1 wt% ramelteon, 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 water. The pharmaceutical composition can be a micellar solution. The wt% means the weight percentage of each component in the total weight of the pharmaceutical composition.

[0044] In an embodiment of the present application, the pharmaceutical composition comprises 0.1-1 wt% ramelteon, 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 water. The pharmaceutical composition can be a micellar solution. The wt% means the weight percentage of each component in the total weight of the pharmaceutical composition.

[0045] In the present application, the preparation method of the pharmaceutical composition can be conventional in the art, and the components are mixed uniformly to obtain the pharmaceutical composition.

[0046] In an embodiment of the present application, the preparation method comprises: mixing the ramelteon with the polyethylene glycol, and then mixing with a mixed solution of other excipients, and finally optionally adding water to 100 wt%. The solvent in the mixed solution of other excipients is water.

[0047] The other excipients can be one or more of the absorption enhancer, the stabilizer, the bacteriostatic agent and the bioadhesive agent.

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

[0049] In the present application, the nasal administration preparation can be conventional in the art, and is preferably a nasal spray.

[0050] In the present application, the nasal administration preparation generally comprises a nasal delivery system, as known by those skilled in the art. The nasal delivery system is preferably a nasal spray device comprising a drug reservoir and a spray pump. In the embodiments of the present application, the spray pump is VP7.

[0051] Positive progress effect: the pharmaceutical composition of the present application has high stability and good atomization effect when prepared into a nasal administration preparation, and can be smoothly sprayed. Compared with oral preparations, the relative bioavailability of the preparation is higher, the onset is faster, and the drug concentration in the target brain tissue is high. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 is the ramelteon drug concentration-time curve in beagles of the nasal spray preparation prepared from the pharmaceutical composition of embodiments 1-3 of the present application.

[0053] Figure 2 is the ramelteon drug concentration-time curve in the brain tissue of rats of the nasal spray preparation prepared from the pharmaceutical composition of embodiment 3 of the present application. DETAILED DESCRIPTION

[0054] In order to make the technical means, creative features, purposes and effects achieved by the invention easy to understand, the present patent will be further described in detail below in combination with the drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present patent, and are not used to limit the present patent.

[0055] Herein, the term "micelle" refers to a molecularly ordered aggregate that forms in large quantities in an aqueous solution when the concentration of a surfactant reaches a certain value. In a micelle, the hydrophobic groups of the surfactant molecules aggregate to form the micellar core, and the hydrophilic polar groups form the outer layer of the micelle. In the art, the addition of polyethylene glycol-12-hydroxystearate to a liquid pharmaceutical composition generally forms a micellar form.

[0056] Herein, the term "in situ gel" refers to a type of preparation that is administered in a solution state and immediately undergoes phase transition at the administration site to form a non-chemically cross-linked semi-solid gel. In the art, the addition of sodium alginate to a liquid pharmaceutical composition generally forms an in situ gel form.

[0057] As used herein, the term "clathrate" refers to a class of organic crystals. The structure of clathrates contains two structural units, i.e. clathrates are composed of two compounds: one is a compound that can confine other compounds in the cavities of its structural framework, referred to as a clathrate or host molecule; the other is a compound that is confined in the cavities or channels of the clathrate structure, referred to as a clathrate or guest molecule. Common compounds that can form cavities or channels include crown ethers, cyclodextrins. In the art, the addition of sulfobutyl-β-cyclodextrin to a liquid pharmaceutical composition generally forms a clathrate form.

[0058] As used herein, the term "nasal spray formulation" refers to a dosage form that exerts a therapeutic effect by injecting a fine mist containing a pharmaceutical active ingredient into the nose through the action of a spray pump.

[0059] In the present application, room temperature generally refers to 15-25°C.

[0060] The viscosity test method of each of the following examples and comparative examples: using a rotational viscosity method, using a Brookfield DV2T rotational viscometer (AMETEK Corporation, USA), selecting a No. 61 rotor, pouring 100 ml of the solution to be tested into the test cup, respectively, and testing the viscosity at a test speed of 150 rpm / min and a test time of 2 min.

[0061] The osmotic pressure test method of each of the following examples and comparative examples: using an osmotic pressure tester to measure the osmotic pressure of the prescription. Take 0.05 mL of the solution to be tested and add it to an EP tube to measure the osmotic pressure value.

[0062] Example 1 Ramelteon micelles

[0063] According to the formulations shown in the following Table 1, ramelteon is dissolved in polyethylene glycol 400 (PEG-400) at 40°C to obtain solution 1, and polyethylene glycol-12-hydroxystearate, benzyl alcohol and disodium edetate are dissolved in 70% by weight of purified water at room temperature to obtain solution 2. After stirring and mixing solution 1 and solution 2, the pH of the mixed solution is adjusted to 5.0 with hydrochloric acid, and finally an appropriate amount of purified water is added for dilution to 100%, i.e. to obtain ramelteon micelles.

[0064] Table 1

[0065]

[0066] The micelle solution prepared using the above formulations and processes is clear, and the test results are as follows: viscosity is 2.6 cP, osmotic pressure is 348 mosmol / kg, and the average particle size D50 of the solution before being loaded into a nasal spray device is 13.07 nm.

[0067] Example 2 Ramelteon in-situ gel

[0068] According to the formulation shown in Table 2 below, rimegepant was dissolved in PEG-400 at 40°C to obtain solution 1, and polyethylene glycol-12-hydroxystearate, benzyl alcohol and sodium alginate were dissolved in 70% purified water at room temperature to obtain solution 2. After mixing solution 1 and solution 2 by stirring, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid, and then the solution was diluted to 100% with purified water, thereby obtaining a rimegepant in-situ gel.

[0069] Table 2

[0070]

[0071] The in-situ gel solution prepared by the above formulation and process was clear, and the test results were as follows: the viscosity was 7.26 cP, the osmotic pressure was 337 mosmol / kg, and the average particle size D50 of the solution before being loaded into a spray device was 13 nm.

[0072] Example 3 Rimegepant inclusion complex

[0073] According to the formulation shown in Table 3 below, rimegepant 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 (solution 2 was kept at 60°C during mixing) at 60°C, and after mixing by stirring, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid, and then the solution was diluted to 100% with purified water, thereby obtaining a rimegepant inclusion complex.

[0074] Table 3

[0075]

[0076] The inclusion complex solution prepared by the above formulation and process was clear, and the test results were as follows: the viscosity was 2.0 cP, the osmotic pressure was 548 mosmol / kg, and the pH was 5.5. The atomized particle size D50 of the solution after being loaded into a nasal spray device (VP7, 50 μL, screw cap) was 44.7 μm.

[0077] Example 4 Rimegepant inclusion complex

[0078] According to the formulation shown in Table 4 below, rimegepant 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 (solution 2 was kept at 60°C during mixing) at 60°C, and after mixing by stirring, the pH of the mixed solution was adjusted to 5.0 with hydrochloric acid, and then the solution was diluted to 100% with purified water, thereby obtaining a rimegepant inclusion complex.

[0079] Table 4

[0080]

[0081] The solution prepared by the above-mentioned formula and process is clear, and the test results show that the osmotic pressure is 340 mosmol / kg. When the solution is filled into a nasal spray device (VP7, 50 μL, screw cap) for administration, the drug can be well atomized into small droplets by the nasal spray device, the spray shape is conical, and the atomization effect is good.

[0082] Example 5 Ramelteon Inclusion Complex

[0083] According to the formula shown in Table 5 below, ramelteon is dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride and disodium edetate are dissolved in purified water 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, and then an appropriate amount of purified water is added for dilution and constant volume to 100%, thereby obtaining a ramelteon inclusion complex.

[0084] Table 5

[0085]

[0086] The solution prepared by the above-mentioned formula and process is clear, and the test results show that the osmotic pressure is 1404 mosmol / kg, and the drug solution can be atomized and normally sprayed out.

[0087] Example 6 Ramelteon Inclusion Complex

[0088] According to the formula shown in Table 6 below, ramelteon is dissolved in PEG-400 at room temperature to obtain solution 1, and sulfobutyl-β-cyclodextrin, benzalkonium chloride and disodium edetate are dissolved in purified water 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, and then an appropriate amount of purified water is added for dilution and constant volume to 100%, thereby obtaining a ramelteon inclusion complex.

[0089] Table 6

[0090]

[0091] The solution prepared by the above-mentioned formula and process is clear, and the test results show that the osmotic pressure is 946 mosmol / kg, and the drug solution can be well atomized into small droplets by the nasal spray device, and the spray shape is conical.

[0092] Example 7 Ramelteon Inclusion Complex

[0093] The ramelteon is dissolved in PEG-400 at room temperature to obtain solution 1, and the sulfobutyl-β-cyclodextrin, benzalkonium chloride and disodium edetate are dissolved in purified water 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, and then diluted to 100% with purified water, to obtain the ramelteon inclusion compound.

[0094] Table 7

[0095]

[0096]

[0097] The solution prepared by the above formulation and process is clear, and the test results are as follows: osmotic pressure is 790 mosmol / kg, the drug solution can be atomized, and can be normally sprayed out.

[0098] Example 8 Rameletone inclusion compound

[0099] The prescription is shown in Table 8 below. The ramelteon is dissolved in PEG-400 at room temperature to obtain solution 1, and the sulfobutyl-β-cyclodextrin, mannitol, benzalkonium chloride and disodium edetate are dissolved in purified water 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, and then diluted to 100% with purified water, to obtain the ramelteon inclusion compound.

[0100] Table 8

[0101]

[0102] The solution prepared by the above formulation and process is clear, and the test results are as follows: osmotic pressure is 992 mosmol / kg, the drug solution can be well atomized into small droplets by the nasal spray device, and the spray shape is conical.

[0103] Comparative Example 1 Ramelteon inclusion compound

[0104] The prescription is shown in Table 9 below. The ramelteon is completely dissolved in propylene glycol, and then the solution is gradually added to the sulfobutyl-β-cyclodextrin solution containing disodium edetate and benzalkonium chloride, and finally an appropriate amount of purified water is added to 1L.

[0105] Table 9

[0106]

[0107] The solution prepared by using the above prescription and process is clear, and the test results are as follows: viscosity is 2.8 cP, osmotic pressure (diluted by 10 times) is 277 mosmol / kg, atomization effect is poor, the size of the sprayed mist is uneven, the liquid spraying distance is obviously lengthened, the spray ovality is narrowed, and normal spraying cannot be performed.

[0108] Comparative Example 2 Ramelteon inclusion compound

[0109] The prescription is shown in Table 10 below, and ramelteon is dissolved in PEG-400 at room temperature to obtain solution 1, HPMC is dissolved in purified water, and sulfobutyl-β-cyclodextrin, benzalkonium chloride and disodium edetate are added to the HPMC solution to be dissolved to obtain solution 2. Solution 1 is added to solution 2 at 60°C, and after stirring and mixing, the mixed solution is adjusted to pH 5.0 with hydrochloric acid, and finally an appropriate amount of purified water is added for dilution to 100%.

[0110] Table 10

[0111]

[0112] The solution is loaded into a nasal spray device (VP7, 50 μL, screw cap), and the atomization effect is poor, and the spray is in the form of a water column.

[0113] Effect Example 1 Stability

[0114] The impurity content in Examples 1-3 is detected by HPLC. The impurities include compounds I and II as shown below:

[0115]

[0116] The HPLC detection method is as follows:

[0117] Chromatographic column: Waters Atlantis T3 (250x4.6mm, 5 microns) or a chromatographic column with equivalent performance;

[0118] Ghost trap column: Welch Ghost-Buster, 4.6x50mm;

[0119] Column temperature: 25°C; flow rate: 1.2 mL / min; detection wavelength: 220 nm; injection volume: 25 microliters; mobile phase: mobile phase A is 0.1% phosphoric acid solution, and mobile phase B is acetonitrile-methanol (6:4), and gradient elution is performed according to Table 11 below.

[0120] Table 11

[0121]

[0122]

[0123] (1) Stability of the micellar formulation of ramelteon

[0124] The micellar solution obtained in Example 1 was filled into a nasal spray device (VP7, 50 μL, screw cap), and the impurity content of the solution after being sprayed from the nasal spray device was measured at 0 day and after being left at high temperature for 10 days using the HPLC detection method described above, and the solution was observed with the naked eye under natural light to obtain the results shown in Table 12 below.

[0125] Table 12

[0126]

[0127] (2) Stability of the in situ gel formulation of ramelteon

[0128] The in situ gel obtained in Example 2 was filled into a nasal spray device (VP7, 50 μL, screw cap), and the impurity content of the solution after being sprayed from the nasal spray device was measured at 0 day and after being left at high temperature for 10 days using the HPLC detection method described above, and the solution was observed with the naked eye under natural light to obtain the results shown in Table 13 below.

[0129] Table 13

[0130]

[0131] (3) Stability of the inclusion complex formulation of ramelteon

[0132] The inclusion complex obtained in Example 3 was filled into a nasal spray device (VP7, 50 μL, screw cap), and the impurity content of the solution after being sprayed from the nasal spray device was measured at 0 day, 1 month and 3 months using the HPLC detection method described above to obtain the results shown in Table 14 below. At the same time, the solution was observed with the naked eye under natural light in each experiment to be a colorless transparent solution.

[0133] Table 14

[0134]

[0135] Note: The accelerated condition is 40°C / 75% RH; the long-term condition is 25°C / 60% RH. 1M and 3M mean 1 month and 3 months, respectively.

[0136] Effect Example 2 Pharmacokinetic study in beagle dogs

[0137] The solutions obtained in Examples 1-3 were filled into nasal spray devices (VP7, 50 μL, screw cap) to obtain three groups of nasal spray formulations, which were named micellar formulation, in situ gel formulation and inclusion complex formulation, respectively, and the pharmacokinetics of each nasal spray formulation in beagle dogs was tested.

[0138] Male beagle dogs were weighed before the experiment and randomly divided into four groups, tablet group, micellar formulation group, in-situ gel formulation group, and inclusion complex formulation group, with 3 dogs in each group. One day before administration, the beagle dogs were fasted overnight. The tablet group was orally administered with 8 mg ramelteon tablets (Rozerem® R ), and the other three groups were administered with 0.4 mg (0.2 mg / spray, left and right one spray) of the micellar formulation, in-situ gel formulation, and inclusion complex formulation, respectively, by nasal spray to the nasal cavity. After administration, the four-limb venous blood was collected at 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, and 4 h, and placed in a labeled EDTA-K2 anticoagulant tube. Within 1 hour after blood collection, the plasma was separated by centrifugation under the conditions of 4°C, 5000g, and 6 min. The separated plasma was placed in a labeled EP tube and subjected to LC-MS / MS analysis to determine the blood drug concentration, as shown in Figure 1 Figure 6, which is the ramelteon drug concentration-time curve of each nasal spray formulation in beagle dogs. The pharmacokinetic parameters were calculated using WinNonlin software, and the results are shown in Table 15 below.

[0139] Table 15

[0140]

[0141] Note: T 1 / 2 refers to the time required for the maximum drug concentration in the plasma to decrease by half; T max is the time to reach the maximum plasma concentration; C max is the maximum plasma concentration; AUC is the area under the plasma concentration-time curve; AUC 0-t refers to the area under the curve at the time point of the last measurable blood drug concentration from the start of administration; "AUC 0-inf " indicates the AUC value from the start of drug administration to time infinity; and nasal spray refers to the administration of the nasal spray formulation to the nasal cavity.

[0142] From the PK results in Table 15, it can be seen that compared with the oral tablet (T max is 0.25 h), the T max of the micellar formulation, in-situ gel formulation, and inclusion complex formulation administered by nasal spray is 0.167 h (10.02 min), 0.083 h (4.98 min), and 0.167 h (10.02 min), respectively, and the onset time is faster. Compared with the oral tablet, the relative bioavailability of the micellar formulation group, in-situ gel formulation group, and inclusion complex group administered by nasal spray is 287%, 228%, and 189%, respectively, which is greatly improved.

[0143] Effect Example 3 Nasal cilia toxicity and rat brain tissue distribution study

[0144] Nasal cilia toxicity: 0.5 mL of the micelle solution prepared in Example 1 and the inclusion complex solution prepared in Example 3 were respectively taken with a pipette and dropped onto the upper jaw of two toads, and after 30 min, the upper jaw mucosa was peeled off to make a slice, which was observed under a microscope. The physiological saline was used as a control group, and the percentage of cilia movement time (i.e. the time required for recording from the start of administration to the complete stop of cilia movement, the control group was 100%, and the relative percentage of the experimental group was calculated). The cilia continuous movement time ratio of the ramelteon inclusion complex of Example 3 was 90.3%, and there was almost no cilia toxicity. The cilia continuous movement time ratio of the ramelteon micelles of Example 1 was 54.6%, and the cilia toxicity was also at a low level.

[0145] Rat brain tissue distribution: The ramelteon inclusion complex prepared in Example 3 was loaded into a nasal spray device (VP7, 50 μL, screw cap) to prepare a nasal spray preparation. The nasal spray preparation was used to study the plasma and brain tissue distribution of SD rats under nasal administration. After the animals were euthanized with CO2, the plasma, cerebrospinal fluid, olfactory bulb and thalamus were collected at 5 min, 15 min, 30 min, 45 min and 60 min after nasal administration. After all the samples were collected, they were transferred to centrifuge tubes, immediately inserted into wet ice, stored in the dark, and subjected to LC-MS / MS analysis within 1 hour. The drug concentration-time curve of the nasal spray preparation in the brain tissue of rats is shown in Figure 6. The experimental results are shown in Table 16. Figure 2

[0146] Table 16

[0147]

[0148] As can be seen from Table 16, after nasal administration, the drug PK of the plasma and thalamus is basically the same, indicating that the drug composition of Example 3 can pass through the blood-brain barrier and reach the brain tissue. According to the public information of the marketed tablet product, when the rats are administered at a dose of 1 mg / kg, the plasma drug concentration C max is 17.5 ng / mL, and the AUC 0-t is 1278 ng / mL*min, and the plasma drug concentration is 4-10 times that of the brain tissue. Calculation shows that the brain tissue C max of oral administration is 1.75-4.38 ng / mL. The drug concentration of the brain tissue of the nasal spray group is 28.7-71.9 times that of the oral brain tissue, indicating that the drug concentration of the brain tissue targeted after nasal administration of the nasal spray preparation of the application is much higher than that of oral administration.

[0149] Effect Example 4 Cynomolgus monkey pharmacokinetic study

[0150] ​The common cynomolgus monkeys were used as the research object, and the ramelteon clathrate of Example 3 was given to the cynomolgus monkeys in the nasal cavity through a nasal spray device (the nasal spray device was VP7, 50 μL, screw mouth), and oral tablets were given by gavage as a control, and blood samples were collected from the limbs at the predetermined time points for detection of relevant pharmacokinetic indexes. A total of 4 groups were divided: a low-dose group (0.2 mg / monkey), a medium-dose group (0.4 mg / monkey), a high-dose group (0.8 mg / monkey), and a tablet group (8 mg / monkey). Blood sample processing: after the sample was removed, it was stored on the surface of crushed ice, and centrifuged within 1 h. The centrifugation conditions were set as follows: 3500 rpm, 2220 x g, 15 min, 4℃. After centrifugation, the supernatant was taken for detection, and the results are shown in Table 17.

[0151] Table 17

[0152]

[0153] The plasma concentration and exposure of ramelteon in cynomolgus monkeys showed an increasing trend with increasing dose. Compared with oral tablets, the relative bioavailability of ramelteon clathrate at different doses was 373% to 482%, which was greatly improved.

[0154] According to the results of rat brain tissue distribution at a dose of 1 mg / kg, the plasma drug concentration after oral administration was 4 to 10 times that of the brain tissue. It can be known that when the cynomolgus monkey was administered at a dose of 8 mg / monkey, the drug concentration in the brain tissue (thalamus) after oral administration was 5.88 to 50 ng / mL. The above-mentioned rat brain tissue distribution results show that the drug PK in the plasma and thalamus after nasal spray administration is basically consistent, and it is concluded that the drug PK in the plasma and thalamus after nasal spray administration (0.4 mg / monkey) in cynomolgus monkeys is consistent, and the drug concentration in the brain tissue after nasal spray administration is about 58.45 ng / mL, which is 23.4 to 198.8 times that of oral administration. Therefore, compared with oral administration, the targeted brain tissue drug concentration after nasal cavity administration of the present application is higher than that of oral administration.

[0155] In summary, the nasal spray preparation prepared from the pharmaceutical composition of the present application not only overcomes the solubility defects of ramelteon, but also solves the problem that the nasal spray preparation cannot be smoothly atomized and sprayed. In the preferred embodiments 1-4, the osmotic pressure is below 600 mosmol / kg without adding additional osmotic pressure regulators, which does not cause damage to the nasal cavity.

[0156] The pharmacokinetics, cilia toxicity, and brain targeting of the nasal spray preparation were further studied, and all had different degrees of excellent effects. Experimental verification showed that the onset time of the preparation was about 5-10 min, the T maxThe onset time is only 4.98 min, which is faster than that of the ramelteon preparations in the prior art; the bioavailability fully demonstrates the advantages of the nasal spray preparation, and is 180%-300% higher than that of the oral preparation. The cilia toxicity is also at a low level, especially the nasal spray preparation containing the cyclodextrin derivative, the cilia sustained movement time ratio is 90.3%, which is much higher than the conventional standard (the greater the cilia sustained movement time ratio, the smaller the toxicity to nasal cilia). The drug concentration targeting the brain tissue is high, and the rat brain tissue distribution results show that the brain tissue drug concentration of the nasal spray group is 30-70 times that of the oral tablet brain tissue. The pharmacokinetic results of cynomolgus monkeys also show that the relative bioavailability of the nasal spray at different doses can reach 350%-500% compared with the oral tablet, and the drug concentration targeting the brain tissue after nasal administration is 20-200 times that of oral administration. In addition, the high relative bioavailability in the pharmacokinetic experiment of beagle dogs and the much higher drug concentration targeting the brain tissue in the rat brain tissue experiment also indirectly prove the low membrane permeability of the drug and the clearance effect of the nasal mucociliary.

[0157] As can be seen from the above, before the scheme of the present application is obtained, some experiments are carried out according to the scheme of the prior art, but none of them can obtain a qualified nasal spray device. For example, in the comparative example 1, propylene glycol is used as a solubilizer, the osmotic pressure is too high, and it cannot be normally sprayed out; and the addition of HPMC can spray out a water column. When polyethylene glycol is selected as an auxiliary material in the preparation of the nasal spray preparation, the solution stability is high, and when the aqueous drug composition is prepared, it can be atomized and smoothly sprayed out in the nasal spray device. Moreover, the contribution of polyethylene glycol to the osmotic pressure is very small, which may be related to the molar concentration of the substance. In theory, 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 be ionized in water, and therefore the osmotic pressure of the solution is 125 mosmol / kg. The molecular weight of propylene glycol is 76, the addition amount is 15 (vol%), and the density is 1.0381 g / cm 3 , the molar concentration = 150 g / L x 1.0381 / 76 (g / mol) = 2049 mmol / L, propylene glycol cannot be ionized in water, and therefore the osmotic pressure of the solution is 2049 mosmol / kg. It is verified by experiments that the osmotic pressure of 5 wt% PEG-400 aqueous solution is 148 mosmol / kg, and the osmotic pressure of 15 vol% propylene glycol aqueous solution diluted by 1 times is 1160 mosmol / kg, which is close to the theoretical calculation value.

[0158] The preferred embodiments of the present application have been described above in detail. It should be understood that modifications and variations to the preferred embodiments could be made by those skilled in the art without departing from the spirit and scope of the application. Accordingly, it is intended that there be included within the scope of the application, all such modifications and variations as would be apparent to those skilled in the art upon reading this disclosure. It is intended to obtain for the inventors such patent rights as are available for any patent granted on the present application.

Claims

1. A pharmaceutical composition comprising ramelteon, characterized in that, which comprises ramelteon and polyethylene glycol.

2. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition is for nasal administration, for example, intranasal mucosal administration; and / or, the pharmaceutical composition is for use in the preparation of a medicament for treating insomnia or alleviating jet lag; and / or, the pharmaceutical composition is in a liquid form, for example, micelles, in-situ gels or clathrates; and / or, the pharmaceutical composition is an aqueous composition; the content of water in the aqueous composition is preferably 65-90% by weight, more preferably 80-85% by weight; and / or, the pharmaceutical composition has an osmotic pressure of 100-900mosmol / kg, preferably 300-600mosmol / kg, for example, 348mosmol / kg, 337mosmol / kg, 548mosmol / kg or 550mosmol / kg; and / or, the pharmaceutical composition has a pH value of 4.5-6.5, for example, 5.5 or 6; and / or, the pharmaceutical composition has a viscosity of 2-8cP, for example, 2.6cP or 7.26cP.

3. The pharmaceutical composition of claim 1, wherein The average molecular weight of the polyethylene glycol is 200-600g / mol, preferably 350-450g / mol, for example, 400g / mol; and / or, the molar concentration of the polyethylene glycol in the pharmaceutical composition is 2-750mmol / L, for example, 100mmol / L, 125mmol / L, 250mmol / L or 300mmol / L, per 1L of the pharmaceutical composition; and / or, the content of the polyethylene glycol is 0.1%-30% by weight, preferably 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, the % by weight referring to the weight percentage of the polyethylene glycol in the total weight of the pharmaceutical composition; and / or, the content of the ramelteon is 0.01%-10% by weight, preferably 0.1-1% by weight, for example, 0.4% by weight or 0.8% by weight, the % by weight referring to the weight percentage of the ramelteon in the total weight of the pharmaceutical composition; and / or, the molar ratio of the ramelteon to the 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 ramelteon 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, 3% by weight or less, 2% by weight or less, 1% by weight or less or 0% by weight of mannitol; and / or, the pharmaceutical composition contains 500mmol / L or less, 400mmol / L or less, 300mmol / L or less, 200mmol / L or less, 100mmol / L or less or 0mmol / L of propylene glycol per 1L of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The pharmaceutical composition further comprises an absorption enhancer; the absorption enhancer comprises a surfactant and / or a cyclodextrin and derivatives thereof; The surfactant is preferably polyethylene glycol-12-hydroxystearate. The cyclodextrin and derivatives thereof are preferably β-cyclodextrin and derivatives thereof and / or γ-cyclodextrin and derivatives thereof; the β-cyclodextrin and derivatives thereof preferably include sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin. The content of the absorption enhancer is preferably 1-60 wt%, more preferably 5-20 wt%, for example 10 wt%, 12 wt% or 15 wt%, the wt% referring to the weight percentage of the absorption enhancer in the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition further comprises a bioadhesive agent; the bioadhesive agent preferably includes one or more of dextran, sucrose, pectin, microcrystalline cellulose, sodium alginate, sodium hyaluronate and chitosan; the bioadhesive agent preferably contains 0.05 wt% or less, 0.01 wt% or less or 0 wt% of non-ionic etherified cellulose, for example hydroxypropyl methylcellulose; the bioadhesive agent is preferably sodium alginate. The content of the bioadhesive agent is preferably 0.01-1 wt%, more preferably 0.01-0.5 wt%, for example 0.1 wt%, the wt% referring to the weight percentage of the bioadhesive agent in the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition further comprises a stabilizer; the stabilizer preferably includes edetate disodium. The content of the stabilizer is preferably 0.01-1 wt%, more preferably 0.01-0.5 wt%, for example 0.1 wt%, the wt% referring to the weight percentage of the stabilizer in the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition further comprises a bacteriostatic agent; the bacteriostatic agent preferably includes one or more of benzalkonium chloride, benzyl alcohol, phenyl ethanol, potassium sorbate and sodium benzoate. The content of the bacteriostatic agent is preferably 0.01-2 wt%, more preferably 0.01-1 wt%, for example 0.07 wt% or 0.5 wt%, the wt% referring to the weight percentage of the bacteriostatic agent in the total weight of the pharmaceutical composition.

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

9. The pharmaceutical composition of any one of claims 1-8, wherein, The preparation method of the pharmaceutical composition comprises the following steps: mixing the ramelteon and the polyethylene glycol, then mixing with a mixed solution of other excipients, and finally supplementing with water to 100% by weight; wherein the other excipients preferably include one or more of the absorption enhancer, the stabilizer, the bacteriostatic agent and the bioadhesive agent.

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

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