FIELD OF THE INVENTION
[0001] The present invention generally relates to apharmaceutical composition of phytochemicals. Specifically, the present invention relates to a dry powder inhalable pharmaceutical composition comprising extracts of microparticles of Alpinia galangal, Curcuma longa and Ficus racemosa. The dry powder inhalable pharmaceutical compositionis useful in the treatment of respiratory problems like asthma, pleuritic and bronchitis.
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] Delivery of drugs has been a major trouble for many years, particularly when the compound to be delivered is unpredictable under the conditions encountered in the gastro-intestinal tract when administered orally to a subject, prior to attainment its targeted location. For example, it is preferable in many cases to administer drugs orally, especially in terms of ease of administration and patient compliance. However, many compounds are ineffective or exhibit low or variable potency when administered orally. Presumably this is because the drugs are unstable to conditions in the digestive tract or because they are inadequately absorbed (Beck-Broichsittere^ al, Journal of Control Release, 2012, 161(2), 214-224;Mehta et al, BiomedPharmacotherapy, 2018, 108: 828-837).
[0004] Due to the nuisance associated with oral drug delivery, drug delivery to the lungs has been explored. Advantages of the lungs for delivery of systemic agents include the large surface area and the ease of uptake by the lung's mucosal surface. Lung diseases are one of the leading causes of death globally, categorized by airflow limitation, loss of elasticity, chronic inflammation, emphysema and mucus hyper secretion. Several factors including genetics, tobacco smoke, air pollution, inhalation of noxious particles and dusts have shown to contribute to the development of lung disease. Some of the most widespread are asthma, chronic obstructive pulmonary disease (COPD), occupational lung diseases and pulmonary hypertension. Main stream allopathic medicines has begun to relocate on herbal medicines as a primary means to deal with critical health problems, also said as 'Back to Mother Nature'

(Tuli et al., Journal of Pharmaceutical Sciences, 2012, 101, 733-744; Chan HK, Journal of Aerosol Medicine, 2006 19(l):21-27).
[0005] The dry powder inhalers (DPIs) are potential drug release systems that could locally introduce the anti-tuberculosis agent to the lung. Compared to the metered-dose inhalers (MDIs), DPIs are more environmentally friendly due to freedom from chlorofluorocarbon (CFC) propellants. However, conventional DPIs present short duration of result and require several doses to be delivered daily. Furthermore, the concentrated drug solution produced in the lung mucosa could irritate the tissue and cause side effects, such as coughing and bronchospasm. Sustaining drug release by employing biodegradable polymers in the fabrication of particles could improve therapeutic outcomes and reduce adverse effects (Zeng et al., International Journal of Pharmaceutics, 2000, 200(1): 93-106). [0006] There is, therefore, a need to develop a dry powder inhalable pharmaceutical composition comprising microparticles of phytochemicals which is suitable for sustained drug release and devoid of side effects.
OBJECTS OF THE INVENTION
[0007] An object of the present invention is to provide a dry powder inhalable
pharmaceutical composition comprising phytochemicals.
[0008] Another object of the present invention is to provide a dry powder inhalable
pharmaceutical composition comprising microparticles of phytochemicals which is devoid of
side effects and suitable for sustained drug release.
[0009] Another object of the present invention is to provide a dry powder inhalable
pharmaceutical composition comprising microparticles of phytochemicals which is useful in
the treatment of respiratory problems like asthma, pleuritic and bronchitis.
[0010] Another object of the present invention is to provide a method for preparation of
dry powder inhalable composition comprising microparticles of phytochemicals.
SUMMARY OF THE INVENTION
[0011] The present invention generally relates to a pharmaceutical composition of phytochemicals. Specifically, the present invention relates to a dry powder inhalable pharmaceutical composition comprising microparticles of extracts of Alpinia galangal, Curcuma longa and Ficus racemosa. The dry powder inhalable pharmaceutical composition is useful in the treatment of respiratory problems like asthma, pleuritic and bronchitis.

[0012] In one aspect, the present invention relates to a dry powder inhalable pharmaceutical composition comprising of:
(a) extractsof Alpinia galangal, Curcuma longa and Ficus racemosa;
(b) a polymer; and
(c) one or more pharmaceutically acceptable carriers.
[0013] In another aspect of the present invention, the polymer of the dry powder
inhalable pharmaceutical composition is natural or synthetic polymer.
[0014] In yet another aspect of the present invention, the polymer of the dry powder
inhalable pharmaceutical composition is polyhydroxybutryate.
[0015] In yet another aspect of the present invention, the extract and polymer in the dry
powder inhalable composition is in the ratio ranges from 1:1 to 1:5.
[0016] In yet another aspect, the present invention relates to a dry powder inhalable
pharmaceutical composition comprising of:
(a) about 30% to 50% of extracts of Alpinia galangal, Curcuma longa and Ficus racemosa;
(b) about 40% to 60% of polymer; and
(c) about 3 % to 20 % of pharmaceutically acceptable carriers.
[0017] In yet another aspect, the present invention relates to a dry powder inhalable pharmaceutical composition comprising of:
(a) about 40% of extracts of Alpinia galangal, Curcuma longa and Ficus
racemosa;
(b) about 55%) of polymer;
(c) about 5 % of pharmaceutically acceptable carriers
[0018] In yet another aspect of the present invention, the dry powder pharmaceutical
composition has aerodynamic diameter of from about 1 um to 15 um.
[0019] In yet another aspect of the present invention, the polymer of the dry powder
inhalable pharmaceutical composition is polyhydroxybutyrate.
[0020] In yet another aspect of the present invention, the one or more pharmaceutically
acceptable carriers of the dry powder pharmaceutical composition is selected from emulsifier,
surfactant, and lubricants.
[0021] In yet another aspect of the present invention, the one or more pharmaceutically
acceptable excipient of the dry powder pharmaceutical composition is selected from leucine
and poloxamer.

[0022] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.
BRIEF DESCRIPTION OF THE FIGURES
[0023] Figure 1 is the normal plots of residual for Daero(urn) of freeze dried ACF-EVIs
(Yl).
[0024] Figure 2 compares the residual vs. run plot for Daero(urn)of freeze dried ACF-EVIs
(Yl)
[0025] Figure 3 compares the predicted vs. actual plot for Daero(urn)of freeze dried ACF-
EVls (Yl)
[0026] Figure 4 depicts the contour plot (2D) showing the effect of independent variables
on Daero(um)of freeze dried ACF-EVIs (Yl) - Emulsifier vs. ACF:PHB
[0027] Figure 5 depicts the contour plot (2D) showing the effect of independent variables
on Daero(um)of freeze dried ACF-EVIs (Yl) - D-Leucine vs. ACF:PHB
[0028] Figure 6 illustrates the contour plot (2D) showing the effect of independent
variables on Daero(urn)of freeze dried ACF-EVIs (Yl) - Emulsifier vs. D-Leucine
DETAILED DESCRIPTION OF THE INVENTION
[0029] 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. [0030] 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." [0031] 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.

[0032] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
[0033] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention 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 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.
[0034] 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.
[0035] All processes 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.
[0036] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0037] 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.
[0038] 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. [0039] 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 thus fulfilling the written description that follows, and the embodiments described herein, 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. [0040] It should also be appreciated that the present invention 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.
[0041] 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.
[0042] In a general embodiment, the present invention relates to a pharmaceutical composition of phytochemicals. Specifically, the present invention relates to a dry powder inhalable pharmaceutical composition comprising extracts of Alpinia galangal, Curcuma longa and Ficus racemosa.
[0043] The term "sustained release" as used herein refers to the dosage form which is not immediate release and is taken to encompass controlled release, prolonged release, timed release, retarded release, extended release and delayed release. Sustained release can be used

interchangeably with prolonged release, programmed release, timed release, extended release,
controlled release and other such dosage forms.
[0044] The term, "therapeutically effective amount" as used herein refers to the amount
of active agent, which halts or reduces the progress of the condition being treated or which
otherwise completely or partly cures or acts palliatively on the condition. A person skilled in
the art can easily determine such an amount by routine experimentation and with an undue
burden.
[0045] The term, "pharmaceutically acceptable" as used herein refers to a carrier
comprised of a material that is not biologically or otherwise undesirable.
[0046] In an embodiment, the present invention relates to adry powder inhalable
pharmaceutical composition comprising of:
(a) extracts oiAlpinia galangal, Curcuma longa and Ficus racemosa;
(b) a polymer; and
(c) one or more pharmaceutically acceptable carriers.
[0047] In another embodiment, the present invention relates to a sustained release pharmaceutical composition comprising of:
(a) about 30% to 50% of extracts oiAlpinia galangal, Curcuma longa and Ficus racemosa;
(b) about 40% to 60% of polymer; and
(c) about3 % to 20 % of pharmaceutically acceptable carriers.
[0048] In another embodiment, the extract ofAlpinia galangal, Curcuma longa and Ficus racemosa(KCF) and the polymeris present in a ratio ranges from 1:1.1 to l:5or vice versa. Preferably, in the ratio selected from 1:1.3, 1:1.5, 1:1.75, 1:2, 1:2.2, 1:2.5, 1:3, 1:3.2, 1:3.5, 1:3.75, 1:4, 1:4.2, 1:4.5 to 1:5. More preferably in the ratio selected from 1:1.3, 1:1.5, 1:1.75, 1:2, 1:2.2 and 1:2.5.
[0049] In another embodiment, the extract ofAlpinia galangal, Curcuma longa and Ficus racemosa(KCF) in the dry powder inhalable composition of the present invention is present in an amount ranges from about 30%> to about 60%> by weight of the pharmaceutical composition. Preferably in an amount of 30%, 35%, 40%, 45%, 50%, 55% and 60% by weight of the composition.More preferably in an an amount of 40%>, 45%>, 50%> and 55%> by weight of the composition.
[0050] In another embodiment, the Alpinia galangal, Curcuma longa and Ficus racemosa (ACF) in the dry powder inhalable composition of the present invention is present in a ratio

ranges from 1:1:1 to 1:5:5 or vice versa. Preferably, present in a ratio of 1:1:1, 1:2:1, 2:1:1, 1:1:2 or 1:2:2.
[0051] In another embodiment, the dry powder pharmaceutical composition ofthe present invention has aerodynamic diameter of lumto 15 um. Preferably, 1.0 um, 1.1 um, 1.2 um, 1.3 um, 1.4 um, 1.5 um, 1.6 um, 1.7 um, 1.8 um, 1.9 um, 2.0 um, 2.1 um, 2.2 um, 2.3 um, 2.4 um, 2.5 um, 2.6 um, 2.7 um, 2.8 um, 2.9 um, 3.0 um, 3.1 um, 3.2 um, 3.3 um, 3.4 um, 3.5 um, 3.6 um, 3.7 um, 3.8 um, 3.9 um, 4.0 um, 4.1 um, 4.2 um, 4.3 um, 4.4 um, 4.5 um, 4.6 um, 4.7 um, 4.8 um, 4.9 um, 5.0 um, 5.1 um, 5.2 um, 5.3 um, 5.4 um, 5.5 um, 5.6 um, 5.7 um, 5.8 um, 5.9 um,6.0 umand so on. Preferably, 1.0 um, 1.1 um, 1.2 um, 1.3 um, 1.4 um,
1.5 um, 1.6 um, 1.7 um, 1.8 um, 1.9 um, 2.0 um, 2.1 um, 2.2 um, 2.3 um, 2.4 um, 2.5 um,
2.5 um, 2.7 um, 2.8 um, 2.9 um, 3.0um, 3.1 um, 3.2 um, 3.3 um, 3.4 um, 3.5 um, 3.6 um, 3.7 um, 3.8 um, 3.9 um and4.0 um.
[0052] In another embodiment, the pharmaceutically acceptable carrier (s) is selected from the group consisting diluents, lubricants, disintegrants, emulsifiers. glidants, surface-active agents, antioxidants, thickeners, suspending agents, flavoring agents, sweeteners, and colorants. The amount of excipient employed will depend upon how much active agent is to be used. One carrier can perform more than one function. In yet another embodiment of the present invention, the diluent of the pharmaceutical composition of the present invention is selected from the group consisting of sugars, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic and calcium sulphate. In another embodiment of the present invention, the lubricant of the pharmaceutical composition of the present invention is selected from the group consisting of talc, magnesium stearate, aluminium stearate, calcium aluminium stearate, zinc stearate, polyethylene glycol, glycerylbehenate, mineral oil, sodium stearylfumarate, stearic acid, and hydrogenated vegetable oil.
[0053] In an embodiment of the present invention, the pharmaceutically acceptable carriers is selected from the group consisting of selected from aspartic acid, glutamic acid, leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine, lysine, PEG 6000, PEG 3000 Tween 80, Poloxamer selected from 188, Poloxamer 407, wherein the amino acid can be either the D configuration, the L configuration or the DL configuration as appropriate to the end use. N-acetyl-L-cysteine, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof.

[0054] In another embodiment, the pharmaceutical^ acceptable carrier is present in an
amount ranges from about 3 % to 15 % by weight of the composition. Preferably, present in
an amount of about 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8% and 10% by weight of
composition. More preferably, present in an amount of about 3%, 3.5%, 4%, 4.5% and 5% by
weight of the composition.
[0055] In another embodiment, the present invention provides a simple and cost-effective
method for preparation of a dry powder inhalable pharmaceutical dosage form comprising a
therapeutically effective amount of ACF. The pharmaceutical composition of the invention
can be formed by various methods known in the art such as by freeze drying, dry granulation,
wet granulation, melt granulation, direct compression, double compression, extrusion
spheronization, layering and the like.
[0056] In yet another aspect, the present invention relates to a dry powder inhalable
composition for the treatment of respiratory diseases selected from asthma, pleuritic,
bronchitis, chronic obstructive pulmonary disease, acute asthma, chronic asthma, severe
asthma, allergic asthma, acute respiratory distress syndrome, infant respiratory distress
syndrome, reversible airway diseases and cystic fibrosis.
[0057] In yet another aspect, in order to deliver a powder to the lungs by oral inhalation
the powder must be packaged into a suitable device. The device must be suitable to aerosolise
the powder during the inhalation process. In an embodiment, the device allows for a dose,
packaged into individual packing, to be inserted into the device prior to delivery. In a yet
another embodiment, the device has a reservoir for delivering multiple doses. In a still further
aspect, a device that has two or more individual doses of powder packaged into individual
packing and assembled or inserted into the device allowing a device to deliver multiple doses.
Suitable devices can be reusable or disposable.
[0058] The dry powder inhalable compositions according to the present invention
comprise the active ingredient in an amount such that, in case of administration by inhalation
from inhalers, the therapeutically effective single dose (hereinafter the single dose) of a
composition of active ingredient is advantageously 10 ug to 500 ug, more advantageously 20
ug to 250ug, preferably 25ug to lOOug, more preferably 25 to 50ug.In an embodiment, the
daily dose may be reached by a single or double administration.
[0059] In another embodiment, the daily dose may be reached by a single administration
and delivered in one actuation of the inhaler.
[0060] In another embodiment, the daily dose may be reached by a single administration
and delivered in more actuations of the inhaler, preferably two.

[0061] In preferred embodiment, the daily dose may be reached by a double
administration and delivered in one actuation of the inhaler.
[0062] In preferred embodiment, the daily dose may be reached by a double
administration and delivered in more actuations of the inhaler, preferably two.
[0063] 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.
[0064] 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.
Methodology
[0065] Composition of freeze dried ACF-EVIs and central composite design (CCD)
layout for fabrication of freeze dried ACF-EVIs have been depicted in Tables 1& 2,
respectively.
Table 1: Independent and response variables for freeze dried ACF-EVIs

Independent variables -1.68 (axial) -1 (Low) 0 (Medium) +1 (High) +1.68 (axial)
X1=*ACF extract: PHB (w/w) 1:1.32 1:2 1:3 1:4 1:4.68
X2 = D-Leucine (% w/v) 0.32 1 2 3 3.68
X3 = Emulsifier (% v/v) 0.66 1 1.5 2 2.34
Response variables Constraint Importance
Yl = Daero (um) Minimize

* Alpinia galangal; Curcuma longa; Ficus racemosa L. extracts in equal proportions
Table 2: Central composite design (CCD) layout for freeze dried ACF-FMs

Batch ACF extract:
PHB (w/w) D-Leucine
(% w/v) Emulsifier
(% v/v)
1 -1 -1 -1
2 1 -1 -1
3 -1 1 -1

4 1 -1
5 -1 -1
6 -1
7 -1 1
8 1
9 -1.68 0 0
10 1.68 0 0
11 0 -1.68 0
12 0 1.68 0
13 0 0 -1.68
14 0 0 1.68
15 0 0 0
16 0 0 0
17 0 0 0
18 0 0 0
19 0 0 0
20 0 0 0
Fabrication of freeze dried ACF-IMs
[0066] Freeze dried ACF-EVIs were prepared by quasi-emulsification solvent evaporation technique followed by freeze drying. ACF extracts and D-Leucinewere dissolved in distilled water followed by addition of poloxamer 407. Organic phase consist of PHB dissolved in dichloromethane which was slowly added to aqueous phase with continuous magnetic stirring (REMI, India) at 2000 rpm for 30 minutes to produce fine dispersion of microparticles succeeded by freeze drying at -55°C and 0.5 kPa (vacuum) for 24 hours (ISIC Make) to generate fine, porous powder having very less density. Determination of microparticles aerodynamic diameter (Daero) (Yl) [0067] The performance of a particle largely depends on its aerodynamic diameter, a parameter which is based on the particle size and density. The particle size of the microparticles was determined using an optical microscopy method. Approximately 100 microparticles were taken on a glass slide and particle size measured using a calibrated optical microscope (Erma, 23 Tokyo, Japan) equipped under regular polarized light. The aerodynamic diameter {Daero) can be expressed as follows

where, pi = 1 g/cm .
Statistical analysis of aerodynamic diameter (Daero) (jini) (Yl) of freeze dried ACF-IMs using quality by design (QbD)
[0068] On the basis of regression coefficient (R2), F-value and p-value calculated by Design-Expert software (Trial Version 11.1.2.0, Stat-Ease Inc., MN), quadratic model was suggested for Yl. The R2, F-value and p-value for Daero (um) were 0.9763, 45.82 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software.
Y = fi0 + ihiPiXi + 2f=i Ai^i2 + Z?=iZf=i+iiWj Eq. (1) where, Y denotes observed response variable and /?o is constant coefficient. /?;, /?;; and /?y represents coefficients of linear, quadratic parameter and interaction parameters, respectively. X[ represents average outcome of changing one variable at a time from low to high, polynomial terms Xt was employed to assess non-linearity effect of variable X, interaction terms XXj illustrated how the response transforms when two variables J^and Xjwere altered concurrently.Daero(|im)of freeze dried ACF-EVIs was synergistically influenced by ACF extract: PHB (XI) whereas antagonistically affected by emulsifier (X3) which can be elucidated by following polynomial quadratic equation.
D-aero(um) = 3.33 +1.57 ACF extract: PHB (w/w) + 0.026 D-Leucine (% w/v)- 0.11 Emulsifier (% v/v) - 0.05 ACF extract: PHB (w/w) * D-Leucine (% w/v) + 0.08 ACF extract: PHB (w/w) * Emulsifier (% v/v) + 0.0012 D-Leucine (% w/v) * Emulsifier (% v/v) + 0.013 ACF extract: PHB (w/w)2 -0.1 D-Leucine (% w/v)2 - 0.24 Emulsifier (% v/v)2Eq. (2)
Table 3: Model Summary Statistics

Source Std. Dev. R2 Adjusted R2 Predicted R2
Linear 0.3409 0.9478 0.9381 0.9135
2FI 0.3701 0.9501 0.9270 0.8556
Quadratic 0.2905 0.9763 0.9550 0.8445 Suggested
Cubic 0.1539 0.9960 0.9874 0.9873 Aliased

Table 4: Lack of Fit Tests

Source Sum of Squares Df Mean Square F-value p-value
Linear 1.72 11 0.1562 5.54 0.0358
2FI 1.64 8 0.2049 7.27 0.0214
Quadratic 0.7031 5 0.1406 4.99 0.0512 Suggested
Cubic 0.0011 1 0.0011 0.0403 0.8488 Aliased
Pure Error 0.1410 5 0.0282
Table 5: ANOVA for Quadratic model for D-aero (urn) (Yl)

Source Sum of Squares Df Mean Square F-value p-value
Model 34.81 9 3.87 45.82 < 0.0001 Significant
XI 33.60 33.60 398.11 < 0.0001
X2 0.0094 0.0094 0.1113 0.7456
X3 0.1792 0.1792 2.12 0.1758
X1X2 0.0231 0.0231 0.2738 0.6122
X1X3 0.0561 0.0561 0.6648 0.4339
X2X3 0.0000 0.0000 0.0001 0.9905
XI2 0.0024 0.0024 0.0281 0.8701
X22 0.1503 0.1503 1.78 0.2116
X32 0.8185 0.8185 9.70 0.0110
Lack of Fit 0.7031 5 0.1406 4.99 0.0512 not significant
[0069] The Model F-value of 45.82 implies the model is significant. There is only a 0.01% chance that an F-value this large could occur due to noise. P-values less than 0.05 indicate model terms are significant. The lack of fit F-value of 4.99 and lack of fit P-value > 0.05 implies best fitting of model. The Predicted R2 of 0.8445 is in reasonable agreement with the Adjusted R2 of 0.9550; i.e., the difference is less than 0.2. Therefore, statistical analysis of Yl can be used to navigate the design space.
Table 6: Diagnostic analysis of aerodynamic diameter (Daero) (um) (Yl) of freeze dried
ACF-EVIs using quality by design (QbD)

Run Actual Value Predicted Residual Externally Studentized

Order (Yl) Value (Yl) Residuals
1 1.36 1.56 -0.1966 -1.204
2 4.69 4.64 0.0549 0.314
3 1.41 1.71 -0.3040 -2.115
4 4.52 4.58 -0.0576 -0.329
5 1.23 1.16 0.0726 0.417
6 4.89 4.57 0.3191 2.278
7 1.28 1.32 -0.0399 -0.227
8 4.73 4.52 0.2116 1.313
9 1.02 0.7343 0.2857 1.714
10 5.70 6.01 -0.3070 -1.890
11 2.86 3.00 -0.1416 -0.761
12 3.21 3.09 0.1203 0.640
13 3.16 2.85 0.3068 1.888
14 2.14 2.47 -0.3281 -2.079
15 3.10 3.33 -0.2344 -0.873
16 3.16 3.33 -0.1744 -0.638
17 3.41 3.33 0.0756 0.272
18 3.36 3.33 0.0256 0.092
19 3.51 3.33 0.1756 0.642
20 3.47 3.33 0.1356 0.492
[0070] Residual is the difference between actual value and software predicted value of any response parameter /.e.Daero (um). Normal plot of residual for Daero (um)of freeze dried ACF-EVIs (Yl) has been plotted between normal % probabilities and externally studentized residuals(Figure 1). The colored points denote the externally studentized residuals for 20 batches of freeze dried ACF-EVIs. Maximum number of colored points lies on a straight line which illustrates normality of data. Figure 2 shows residual vs. run plot for Daero (um)of freeze dried ACF-EVIs (Yl). Colored points lie within a range of ±4 (indicated as red colored line in figure) which signify that residuals lie within an optimum range. Figure 3 shows predicted vs. actual plot for Daero (um)of freeze dried ACF-EVIs (Yl). Colored points lying around the straight line illustrated insignificant difference between actual and software predicted values of Daero (nm). Figure 4 represents contour plot (2D) showing the effect of

ACF extract: PHB (w/w) (XI) and emulsifier (% v/v) (X3) on Daero (um) of freeze dried ACF-EVIs (Yl). Figure 4 illustrates that Daero (fim) of ACF-EVIs gets increased with increase in ACF extract: PHB while it gets decreased with increase in emulsifier concentration which might be owing to interfacial effect of emulsifier. Figure 5 represents contour plot (2D) showing the effect of ACF extract: PHB (w/w) (XI) and D-Leucine (% w/v) (X2) on Daero (um)of freeze dried ACF-EVIs (Yl). Figure 5 illustrates that Daero (um) of ACF-EVIs gets increased with increase in ACF extract: PHB and amount of D-Leucine (% w/v). Figure 6 represents contour plot (2D) showing the effect of D-Leucine (% w/v) (X2) and emulsifier (% v/v) (X3) on Daero (um)of freeze dried ACF-EVIs (Yl). Figure 6 also illustrates that Daero (um) of ACF-EVIs gets increased with increase in amount of D-Leucine (% w/v). [0071] Composition of the present invention

S.No Ingredient Amount used
during
manufacturing % weight of
ingredient
during
manufacturing
procedure % weight of ingredients in optimized product [IMs (dry solid form)]
1 Extract lg 1% w/v in aqueous phase 17.18%
2 PHB 1.32g 1.32% w/v in organic phase 22.68%
3 D-Leucine 2g 2% w/v in aqueous phase 34.36%
4 Poloxamer 407 l-5g 1.5% v/v in aqueous phase 22.77%
Total -100
[0072] Freeze dried ACF-EVIs were prepared by quasi-emulsification solvent evaporation technique followed by freeze drying. ACF extracts and D-Leucine were dissolved in distilled water followed by addition of poloxamer 407. Organic phase consist of PHB dissolved in dichloromethane which was slowly added to aqueous phase with continuous magnetic stirring (REMI, India) at 2000 rpm for 30 minutes to produce fine dispersion of microparticles succeeded by freeze drying at - 55oC and 0.5 kPa (vacuum) for 24 hrs (ISIC Make) to generate fine, porous powder having very less density.
% Yield, moisture content and Carr's index (%) of the dry powder composition of present invention were found to be 72.85 %, < 1% and 13 %, respectively.

[0073] A skilled artisan will appreciate that the quantity and type of each ingredient including the medicinal plant can be used in different combinations or singly. All such variations and combinations would be falling within the scope of present disclosure [0074] 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.

We Claim

1.A dry powder inhalable pharmaceutical composition comprising of:
(a) extracts o£ Alpinia galangal, Curcuma longa and Ficus racemosa;
(b) a polymer; and
(c) one or more pharmaceutically acceptable carriers.

2. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the polymer is natural or synthetic polymer.
3. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the polymer is polyhydroxybutryate.
4. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the extract and polymer is in the ratio ranges from 1:1 to 1:5.
5. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the composition comprises:
(a)about30% to 50% of extracts of Alpinia galangal, Curcuma longa and Ficus racemosa;
(b) about 40% to 60% of polymer;
(c) about 3 % to 20 % of pharmaceutically acceptable carriers.
6. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the
composition comprises:
(a) about 40% of extracts of Alpinia galangal, Curcuma longa and Ficus
racemosa;
(b) about 55%) of polymer;
(c) about 5 % of pharmaceutically acceptable carriers.

7. The dry powder inhalable pharmaceutical composition as claimed in any one of the claims 1 to 6, wherein the composition has aerodynamic diameter of from about 1 um to 15 um:
8. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the polymer is polyhydroxybutyrate.
9. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable carriers is selected from emulsifier, surfactant and lubricants.

10. The dry powder inhalable pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient is selected from leucine and poloxamer.