FIELD OF THE INVENTION
[0001] The present disclosure relates generally to pharmaceutical compositions. More specifically, the disclosure is directed to a microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, mannitol, polyvinylpyrrolidone and an emulsifier. The present disclosure also provides a process of manufacturing the microparticles-based composition.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine) is an imidazole derivate and active d-isomer of medetomidine with analgesic, anxiolytic and sedative properties. Dexmedetomidine selectively binds to pre-synaptic alpha-2 adrenoceptors located in the brain, thereby inhibiting the release of norepinephrine from synaptic vesicles. Dexmedetomidine is a relatively selective alpha 2- adrenergic agonist with sedative properties. Adrenergic receptors are membrane-bound proteins that mediate the peripheral and central actions of norepinephrine and epinephrine. Dexmedetomidine causes activation of inhibitory action of G-proteins which result into decrease in cyclic AMP, activates G proteins which directly act on membrane bound ion channels, mainly on potassium channels and also cause inhibition of noradrenaline release within neuronal tissue, activate nitric oxide and cyclic GMP pathway. Dexmedetomidine is used as an adjuvant for premedication, especially in patients susceptible to preoperative and perioperative stress because of its sedative, anxiolytic, analgesic, sympatholytic, and stable hemodynamic profile. Dexmedetomidine is notable for its ability to provide sedation without risk of respiratory depression (unlike other commonly used drugs such as propofol and fentanyl) and can provide cooperative or semi-rousable sedation.
[0004] However, Dexmedetomidine undergoes near complete hepatic metabolism to inactive metabolites, hence, oral administration of Dexmedetomidine is not feasible due to bioavailability concern. Therefore, there is a need in the art to develop compositions of Dexmedetomidine that provide alternative routes of drug delivery and overcome the hepatic metabolism of the drug.

OBJECTS OF THE INVENTION
[0005] An object of the present disclosure is to provide a microparticles-based inhalable pharmaceutical composition that avoids the hepatic metabolism of Dexmedetomidine.
[0006] Another object of the present disclosure is to provide a pharmaceutical composition of Dexmedetomidine that has microparticles with low particle size and bulk density that enables deeper penetration to give desired pharmacological action.
[0007] Yet another object of the present disclosure is to provide a process of manufacturing a microparticles-based inhalable pharmaceutical composition.

SUMMARY OF THE INVENTION
[0008] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0009] Aspects of the present disclosure provide a composition of 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole that avoids hepatic metabolism of the drug and improves its bioavailability in the physiological environment.
[0010] In an aspect, the present disclosure provides a microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, and an emulsifier.
[0011] In an embodiment, the composition comprises 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in a range of about 2%w/w to about 8%w/w of the composition.
[0012] In an embodiment, mannitol may be present in a weight by weight ratio range of about 1:5 to about 1:25 with respect to 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
[0013] In an embodiment, polyvinylpyrrolidone acts as a polymer for the composition and may be present in a weight by weight ratio of about 1:2 to about 1:4 with respect to the drug, 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
[0014] In an embodiment, the emulsifier may be selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan monolaurate (span 20), sorbitan monopalmitate (span 40), sorbitan stearate (span 60), sorbitane monooleate (span 80), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), or combinations thereof.
[0015] In an embodiment, the emulsifier may be present in a range of about 0.5 %v/v to about 2.5%v/v of the composition.
[0016] In an embodiment, the composition may be a lyophilized microparticles-based inhalable pharmaceutical composition.
[0017] In an aspect, the present disclosure provides a microparticles-based inhalable pharmaceutical formulation comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, an emulsifier, and optionally one or more additive(s).
[0018] In another aspect, the present disclosure provides an inhaler comprising a microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, and an emulsifier.
[0019] In yet another aspect, the present disclosure provides a process of manufacture of a lyophilized microparticles-based inhalable pharmaceutical composition, wherein the process comprises the steps of: (a) dissolving 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, mannitol, and emulsifier in water to produce an aqueous phase; (b) dissolving polyvinylpyrrolidone in an organic solvent to produce an organic phase; and (c) transferring the aqueous phase slowly into the organic phase with stirring for solvent evaporation at about 1000rpm to about 2000rpm and lyophilizing to give the composition.
[0020] Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
[0022] Figure 1 provides the effect of various factors on mean diameter (µm) (Y1) of a composition as per an embodiment of the present disclosure. Figure 1(a) provides the contour plot of the effect of stirring speed (rpm) (X2) and drug : polymer ratio (w/w) (X1) on mean diameter (µm) (Y1) of the composition. Figure 1(b) provides the response surface plot of the effect of stirring speed (rpm) (X2) and drug : polymer ratio (w/w)(X1) on mean diameter (µm) (Y1) of the composition. Figure 1(c) provides the contour plot of the effect of emulsifier (%v/v) (X3) and drug : polymer ratio (w/w)(X1) on mean diameter (µm) (Y1) of the composition. Figure 1(d) provides the response surface plot of the effect of emulsifier (%v/v) (X3) and drug : polymer ratio (w/w) (X1) on mean diameter (µm) (Y1) of the composition.
[0023] Figure 2 provides the effect of various factors on bulk density (g/cc) (Y2) of a composition as per an embodiment of the present disclosure. Figure 2(a) provides the contour plot of the effect of stirring speed (rpm) (X2) and drug : polymer ratio (w/w) (X1) on bulk density (g/cc) (Y2) of the composition. Figure 2(b) provides the response surface plot of the effect of stirring speed (rpm) (X2) and drug : polymer ratio (w/w)(X1) on bulk density (g/cc) (Y2) of the composition. Figure 2(c) provides the contour plot of the effect of emulsifier (%v/v) (X3) and drug : polymer ratio (w/w)(X1) on bulk density (g/cc) (Y2) of the composition. Figure 2(d) provides the response surface plot of the effect of emulsifier (%v/v) (X3) and drug : polymer ratio (w/w) (X1) on bulk density (g/cc) (Y2) of the composition.
[0024] Figure 3 provides the (a) contour plot and (b) response surface plot of the effect of emulsifier (%v/v) (X3) and drug:polymer (w/w) (X1) on desirability for the composition, as per an embodiment of the present disclosure.
[0025] Figure 4 provides a graph for cumulative drug release (%) with time (minutes), i.e. In vitro drug release profile of Dexmedetomidine, in phosphate buffer pH 7.4 for (a) pure drug Dexmedetomidine; (b) physical mixture of drug Dexmedetomidine, mannitol, PVP K-30, and Tween® 20 and (c) composition of Dexmedetomidine as per an embodiment of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION
[0026] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0027] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0028] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0029] In some embodiments, numbers have been used for quantifying amounts, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0030] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0031] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0032] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0033] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0034] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0035] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0036] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0037] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0038] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0039] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0040] As described herein, the term ‘effective amount’ refers to the amount of the composition required to bring about a change or improvement in a subject without side effects or overdosing.
[0041] The term, "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm-blooded vertebrate animals of the class 'mammalia' , including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young, the term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0042] In an embodiment, the present disclosure provides a microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, and an emulsifier.
[0043] In an embodiment, the composition comprises 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in a range of about 2%w/w to about 8%w/w of the composition. In a preferred embodiment, the composition comprises 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in a range of about 4%w/w to about 5%w/w of the composition.
[0044] In some embodiments, the composition may comprise any pharmaceutically acceptable salts, solvates or hydrates of Dexmedetomidine well-known in the art. Suitable pharmaceutically acceptable salts or hydrates may include Dexmedetomidine hydrochloride, Dexmedetomidine anhydrous, Dexmedetomidine monohydrate, or combinations thereof.
[0045] In an embodiment, mannitol may be present in a weight by weight ratio range of about 1:5 to about 1:25 with respect to 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, preferably in a ratio of about 1:20 with respect to 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
[0046] In an embodiment, polyvinylpyrrolidone acts as a polymer for the composition and may be present in a weight by weight ratio of about 1:2 to about 1:4 with respect to the drug, 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Preferably the polyvinylpyrrolidone is polyvinylpyrrolidone K-30 (PVP K-30) present in a weight by weight ratio of about 1:2.1 with respect to the drug, 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
[0047] In an embodiment, the emulsifier may be selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan monolaurate (span 20), sorbitan monopalmitate (span 40), sorbitan stearate (span 60), sorbitane monooleate (span 80), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), or combinations thereof; preferably the emulsifier is polyoxyethylene (20) sorbitan monolaurate or polysorbate 20.
[0048] In an embodiment, the emulsifier may be present in a range of about 0.5 %v/v to about 2.5%v/v of the composition. In a preferred embodiment, the composition comprises emulsifier in a range of about 1%v/v to about 2%v/v of the composition.
[0049] In an embodiment, the composition may be a lyophilized microparticles-based inhalable pharmaceutical composition.
[0050] In a preferred embodiment, the composition is a lyophilized microparticles-based inhalable pharmaceutical composition comprising 0.5mg of 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, 10mg of mannitol, 1.05mg of polyvinylpyrrolidone, and 0.05mg of the emulsifier.
[0051] The composition is physically and chemically stable.
[0052] In contrast to parenterals, inhalation route provides better patient compliance. The present disclosure provides polymeric inhalable microparticles of Dexmedetomidine for drug delivery through inhalation route which could avoid hepatic metabolism and thus, would exhibit desired pharmacological action such as sedative, anxiolytic, and/or analgesic effects.
[0053] The microparticles of the composition possess reduced particle size and lesser bulk density which are required for systemic drug absorption and pharmacological action via inhalation route.
[0054] In some embodiments, the composition possesses microparticles with mean diameter of about 2µm. The mean diameter of the microparticles in the composition is dependent on the w/w drug to polymer ratio, i.e., 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole to polyvinylpyrrolidone ratio and the amount of emulsifier present in the composition.
[0055] In some embodiments, the composition possesses microparticles with bulk density of about 0.4g/cc. The bulk density of the microparticles in the composition is dependent on the w/w drug to polymer ratio, i.e., 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole to polyvinylpyrrolidone ratio.
[0056] The composition possesses synergism in that the composition shows up to 2.4 folds increase in in vitro dissolution of Dexmedetomidine compared to a mere admixture of Dexmedetomidine, mannitol, polyvinylpyrrolidone, and an emulsifier.
[0057] The composition also shows technical advancement in terms of up to 2.4 folds increase in in vitro dissolution of Dexmedetomidine from the present composition compared to pure drug- Dexmedetomidine.
[0058] In an embodiment, the present disclosure provides a microparticles-based inhalable pharmaceutical formulation comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, an emulsifier, and optionally one or more additive(s).
[0059] In an embodiment, the additive(s) may be selected from lubricant, anti-adherent, diluents, additional carrier, flavoring agents, or combinations thereof. In an embodiment, the additive(s) may be selected from sorbitol, lecithin, magnesium stearate, stearic acid, maltose, sucrose, glucose, or combinations thereof. However, a person of skill in the art would understand that any other additive(s) may be employed in the formulation without going beyond the scope of the present disclosure.
[0060] In an embodiment, the formulation may be in a form suitable for nasal delivery of the drug. In an embodiment, the formulation is suitable for inhalation. In a preferred embodiment, the formulation may be in the form of a powder or pellets.
[0061] In an embodiment, the present disclosure provides an inhaler comprising a microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, and an emulsifier.
[0062] In some embodiments, the inhaler may release 11.6mg of the composition per puff. The inhaler may be a single dose inhaler or multi-dose inhaler.
[0063] In an embodiment, the inhaler may comprise one or more other therapeutically active agent(s). The other therapeutically active agent may be a potent respiratory agent for respiratory diseases that may be co-mixed or co-lyophilized while forming the formulation.
[0064] In an embodiment, the present disclosure provides a medicament comprising the microparticles-based inhalable pharmaceutical composition as recited above.
[0065] In an embodiment, the present disclosure provides use of a microparticles-based inhalable pharmaceutical composition as an adjuvant for premedication, especially in patients susceptible to preoperative and perioperative stress, or other sedative, anxiolytic, analgesic, sympatholytic or combinatorial purposes.
[0066] In an embodiment, the composition may be provided in an effective amount suitably chosen by a medical professional based on a subject.
[0067] In an embodiment, the microparticles-based inhalable pharmaceutical composition may be manufactured using a combination of solvent evaporation and lyophilization.
[0068] In an embodiment, the present disclosure provides a process of manufacture of a lyophilized microparticles-based inhalable pharmaceutical composition, wherein the process comprises the steps of: (a) dissolving 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, mannitol, and emulsifier in water to produce an aqueous phase; (b) dissolving polyvinylpyrrolidone in an organic solvent to produce an organic phase; and (c) transferring the aqueous phase slowly into the organic phase with stirring for solvent evaporation at about 1000rpm to about 2000rpm and lyophilizing to give the composition.
[0069] In an embodiment, the organic solvent may be selected from ethanol, methanol, acetone, ethyl acetate, acetic acid or combinations thereof.
[0070] Preferably, the stirring may be performed at about 1500 rpm to 2000 rpm for about 30 minutes and the lyophilization may be performed at -55oC and 0.5 kPa (vacuum) for about 24 hrs to generate a fine, porous powder of lyophilized microparticles-based inhalable pharmaceutical composition having very less density. The microparticles produced have good homogeneity. Any lyophilizer well-known in the art may be employed without going beyond the spirit and scope of the present disclosure.
[0071] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0072] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
[0073] Materials: Dexmedetomidine was obtained from INTAS Pharmaceuticals Ltd., Ahmedabad while mannitol, polyvinyl pyrollidone K-30 (PVP K-30) and Tween® 20 were obtained from LOBA chemical Pvt. Ltd., Mumbai.
[0074] EXAMPLE 1: Manufacture of the composition
[0075] Various compositions of the lyophilized microparticles-based inhalable pharmaceutical composition were synthesized using a combination of solvent evaporation and lyophilization technique. For each batch, 100 doses of the composition of Dexmedetomidine were synthesized considering 500 µg Dexmedetomidine (drug) per inhalation (i.e. for 100 doses, 50 mg Dexmedetomidine). The ratio of Dexmedetomidine and mannitol was kept constant (1:20). The quantities of PVP K-30(polymer) and Tween®20(emulsifier) were varied as mentioned in Tables 1 and 2. Dexmedetomidine, mannitol and Tween®20 were dissolved in distilled water to produce aqueous phase. PVP K-30 was dissolved in ethanol to produce organic phase. The aqueous phase was transferred slowly into the organic phase and stirred using magnetic stirring (REMI, India) at 2000 rpm for 30 minutes to evaporate the solvents succeeded by lyophilization at -55oC and 0.5 kPa (vacuum) (ISIC Make) for 24 hrs to generate fine, porous powder. The synthetic molecule encapsulated into lyophilized microparticles inhalable composition was further optimized using Box-Behnken design (BBD) to produce compositions with reduced particle size and lesser bulk density.
Table 1: Factors and response parameters considered for production of composition
Factors -1 (Low) 0 (Medium) +1 (High)
X1= Drug: Polymer (w/w) 1:2 1:3 1:4
X2 = Stirring Speed (rpm) 1000 1500 2000
X3 = Emulsifier (% v/v) 0.5 1 1.5
Response parameters Constraints Importance
Y1 = Mean Diameter (µm) Minimize +++++
Y2 = Bulk Density (g/cc) Minimize +++++

Table 2: Box-Behnken design (BBD) layout for different batches of composition
Batch X1 X2 X3 Y1 Y2
C-1 -1 -1 0 2.8 0.5
C-2 +1 -1 0 8.8 0.9
C-3 -1 +1 0 2.5 0.53
C-4 +1 +1 0 8.3 0.88
C-5 -1 0 -1 3.3 0.54
C-6 +1 0 -1 8.6 0.91
C-7 -1 0 +1 1.9 0.42
C-8 +1 0 +1 8.1 0.89
C-9 0 +1 +1 5.2 0.53
C-10 0 +1 -1 4.8 0.64
C-11 0 -1 +1 4.4 0.58
C-12 0 -1 -1 4.6 0.52
C-13 0 0 0 4 0.5
C-14 0 0 0 4.2 0.67
C-15 0 0 0 4.4 0.54
C-16 0 0 0 4.2 0.59
C-17 0 0 0 4.1 0.52

[0076] Evaluation of mean diameter and bulk density of the compositions:
[0077] A) Evaluation of mean diameter (µm) (Y1): The mean diameters were determined using an optical microscope outfitted with an ocular micrometer calibrated with stage micrometer. An overall of 100 microparticless were observed to determine mean diameter. The observations were performed in triplicate (n = 3).
[0078] Statistical and response surface analysis of mean diameter (µm) (Y1): Statistical analysis of mean diameter (µm) (Y1) was performed using analysis of variance using Design-Expert software, and the results are shown in Tables 3, 4 and 5. The R², F-value and p-value for mean diameter (µm) (Y1) were 0.9967, 238.42 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software.
Y1= 4.18 + 2.91X1 – 0.125X2 – 0.3625X3 – 0.05X1X2 + 0.225X1X3 + 0.15X2X3 + 1.07X12 + 0.347X22 + 0.2225X32
[0079] The positive and negative signs indicated before X1, X2 and X3 depicts synergistic amd antagonistic effect of factors on Y1. Model F-value 238.42 (p < 0.05) and lack of fit F-value 2.39 (p > 0.05) for Y1 implicated that the model was significant with a noise factor of only 0.01%. The results evidently specified that X1 and X3 have significant effect on mean diameter (µm) (Y1). The relationship between factors and responses can be inferred by contour and response surface plots, as shown in Figure 1.
Table 3: Model summary statistics of mean diameter (µm) (Y1) of composition
Source Std. Dev. R² Adjusted R² Predicted R² PRESS
Linear 0.7052 0.9144 0.8946 0.8600 10.57
2FI 0.7850 0.9184 0.8694 0.7439 19.33
Quadratic 0.1873 0.9967 0.9926 0.9648 2.66 Suggested
Cubic 0.1483 0.9988 0.9953 - * Aliased

Table 4: Lack of fit tests of mean diameter (µm) (Y1) of composition
Source Sum of Squares df Mean Square F-value p-value
Linear 6.38 9 0.7085 32.21 0.0022
2FI 6.07 6 1.01 46.02 0.0012
Quadratic 0.1575 3 0.0525 2.39 0.2099 Suggested

Table 5: Analysis of variance (ANOVA) of mean diameter (µm) (Y1) of composition
Source Sum of Squares Df Mean Square F-value p-value
Model 75.26 9 8.36 238.42 < 0.0001 significant
X1 67.86 1 67.86 1934.94 < 0.0001 significant
X2 0.1250 1 0.1250 3.56 0.1010 not significant
X3 1.05 1 1.05 29.97 0.0009 significant
X1X2 0.0100 1 0.0100 0.2851 0.6099 not significant
X1X3 0.2025 1 0.2025 5.77 0.0473 Significant
X2X3 0.0900 1 0.0900 2.57 0.1532 not significant
X1² 4.84 1 4.84 138.09 < 0.0001 Significant
X2² 0.5084 1 0.5084 14.50 0.0066 Significant
X3² 0.2084 1 0.2084 5.94 0.0449 Significant
Lack of Fit 0.1575 3 0.0525 2.39 0.2099 not significant

[0080] B) Evaluation of bulk density (g/cc) (Y2): The bulk density was determined using 10 mL graduated cylinder. 1 gram of sample was poured into the cylinder and bulk density was calculated using equation 1.
Eq.1
[0081] Statistical and response surface analysis of bulk density (g/cc) (Y2): Statistical analysis was performed using analysis of variance using Design-Expert software, and the results are shown in Tables 6, 7 and 8. The R², F-value and p-value for bulk density (g/cc) (Y2) were 0.9522, 15.48 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software.
Y2= 0.564 + 0.1988X1 + 0.0075X2 – 0.0263X3 ¬– 0.0125X1X2 + 0.025X1X3 – 0.0425X2X3 + 0.1305X12 + 0.008X22 – 0.0045X32
[0082] The positive and negative signs indicated before X1, X2 and X3 depicts synergistic amd antagonistic effect of factors over Y2. Model F-value 15.48 (p < 0.05) and lack of fit F-value 0.1314 (p > 0.05) for Y2 implicated that the model was significant with a noise factor of only 0.01%. The results evidently specified that X1 has significant effect on bulk density (g/cc) (Y2). The relationship between factors and responses can be inferred by contour and response surface plots, as shown in Figures 2.
Table 6: Model summary statistics of bulk density (g/cc) (Y2) of composition
Source Std. Dev. R² Adjusted R² Predicted R² PRESS
Linear 0.0892 0.7570 0.7009 0.5783 0.1794
2FI 0.0965 0.7813 0.6501 0.2383 0.3240
Quadratic 0.0539 0.9522 0.8907 0.8633 0.0581 Suggested
Cubic 0.0680 0.9565 0.8258 * Aliased

Table 7: Lack of fit tests of bulk density (g/cc) (Y2) of composition
Source Sum of Squares df Mean Square F-value p-value
Linear 0.0849 9 0.0094 2.04 0.2571
2FI 0.0745 6 0.0124 2.68 0.1794
Quadratic 0.0018 3 0.0006 0.1314 0.9364 Suggested

Table 8: Analysis of variance (ANOVA) of bulk density (g/cc) (Y2) of composition
Source Sum of Squares df Mean Square F-value p-value
Model 0.4050 9 0.0450 15.48 0.0008 significant
X1 0.3160 1 0.3160 108.73 < 0.0001 significant
X2 0.0005 1 0.0005 0.1548 0.7057 not significant
X3 0.0055 1 0.0055 1.90 0.2109 not significant
X1X2 0.0006 1 0.0006 0.2150 0.6569 not significant
X1X3 0.0025 1 0.0025 0.8602 0.3846 not significant
X2X3 0.0072 1 0.0072 2.49 0.1589 not significant
X1² 0.0717 1 0.0717 24.67 0.0016 significant
X2² 0.0003 1 0.0003 0.0927 0.7696 not significant
X3² 0.0001 1 0.0001 0.0293 0.8689 not significant
Lack of Fit 0.0018 3 0.0006 0.1314 0.9364 not significant

[0083] Based on the above values, the optimized values of each of the constituents in the composition were arrived at as shown in Tables 9 and 10. Figure 3 provides the contour plot and response surface plot of the effect of emulsifier (%v/v) (X3) and drug:polymer (w/w) (X1) on desirability for the composition.
Table 9: Values of variables for production of optimized composition
Independent variables Criteria Value Desirability function
X1= Drug: Polymer (w/w) In range 1 : 2.1 -
X2 = Stirring Speed (rpm) In range 1578
X3 = Emulsifier (Tween® 20) (% v/v) In range 1.47
Response variables
Y1 = Mean Diameter (µm) Minimize 2.1 0.881
Y2 = Bulk Density (g/cc) Minimize 0.437

Table 10: Final optimized composition of Dexmedetomidine for 100 doses (Dexmedetomidine 500 µg per inhalation)
Composition components Amount
Dexmedetomidine 50 mg
Mannitol 1000 mg
PVP K-30 105 mg
Tween® 20 5 mg
Total inhalation product for 100 doses 1160 mg
Total inhalation product per puff 11.6 mg

[0084] EXAMPLE 2: In vitro dissolution studies
[0085] Dissolution studies were performed using USP II Paddle dissolution apparatus. The goal of the dissolution study was to illustrate the improvement in dissolution rate of Dexmedetomidine in various compositions of the present disclosure over pure drug. In vitro dissolution studies were carried out on the composition of Table 10 at 37°C (± 0.5°C) at 100 rpm in phosphate buffer (pH 7.4) with USP Dissolution Apparatus II (LABINDIA DF8000). For comparison, dissolution studies were also performed with (a) pure drug (Dexmedetomidine), and (b) a physical mixture of the drug Dexmedetomidine with inactive/excipients i.e., PVP K-30, mannitol and Tween®20.
[0086] The percentage cumulative drug release from pure drug, physical mixture and Dexmedetomidine composition as per the present disclosure at 180 minutes was 34.28±1.94%, 37.84±2.83% and 96.37±3.29 %, respectively. A plot for the in vitro dissolution profile of the three cases has been provided in Figure 4. Therefore, in vitro dissolution profile illustrates that percentage drug release in phosphate buffer (pH 7.4) from microparticles-based inhalable pharmaceutical composition comprising Dexmedetomidine was increased approximately 2.8-fold times, which indicates improvement in aqueous solubility and therefore, increased bioavailability of microparticles of Dexmedetomidine.
[0087] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
[0088] The present disclosure provides a microparticles-based inhalable pharmaceutical composition for Dexmedetomidine wherein the microparticles have low particle size and bulk density to increase its systemic absorption and pharmacological action via inhalation route.
[0089] The present disclosure provides a microparticles-based inhalable pharmaceutical composition that has high patient compliance compared to other oral delivery systems.

We Claims:

1. A microparticles-based inhalable pharmaceutical composition comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, mannitol, polyvinylpyrrolidone, and an emulsifier.
2. The composition as claimed in claim 1, wherein the composition comprises 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in a range of 2%w/w to 8%w/w of the composition.
3. The composition as claimed in claim 1, wherein mannitol is present in a weight by weight ratio range of 1:5 to 1:25 with respect to 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
4. The composition as claimed in claim 1, wherein polyvinylpyrrolidone is present in a weight by weight ratio of 1:2 to 1:4 with respect to the drug, 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.
5. The composition as claimed in claim 1, wherein the emulsifier is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan monolaurate (span 20), sorbitan monopalmitate (span 40), sorbitan stearate (span 60), sorbitane monooleate (span 80), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), or combinations thereof.
6. The composition as claimed in claim 1, wherein the emulsifier is present in a range of 0.5 %v/v to 2.5%v/v of the composition.
7. The composition as claimed in claim 1, wherein the composition is a lyophilized microparticles-based inhalable pharmaceutical composition.
8. A microparticles-based inhalable pharmaceutical formulation comprising 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (Dexmedetomidine), mannitol, polyvinylpyrrolidone, an emulsifier, and optionally one or more additive(s).

9. An inhaler comprising a microparticles-based inhalable pharmaceutical composition as claimed in claim 1.
10. A process of manufacture of a lyophilized microparticles-based inhalable pharmaceutical composition, wherein the process comprises the steps of: (a) dissolving 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, mannitol, and emulsifier in water to produce an aqueous phase; (b) dissolving polyvinylpyrrolidone in an organic solvent to produce an organic phase; and (c) transferring the aqueous phase slowly into the organic phase with stirring for solvent evaporation at 1000rpm to 2000rpm and lyophilizing to give the composition.