Formulation and Development of a “Pressurised Metered Dose Inhalation” beclomethasone 250 mcg.

 

Sandesh More^1*, Javed Mirza² , Nanasaheb Kale³, Mayur Gandhi⁴, Rakesh Chaudhari⁵

¹Department of Pharmaceutics, M.G.V. College of Pharmacy, Panchavati, Nashik-422003, Maharashtra, India.

²Department of Quality Assurance Techniques, M.V.P. Samaj’s College of Pharmacy, Near K.T.H.M. Campus, Gangapur road, Nashik-422002, Maharashtra, India.

³Department of Pharmaceutical Chemistry, M.V.P. Samaj’s College of Pharmacy, Near K.T.H.M. Campus, Gangapur road, Nashik-422002, Maharashtra, India.

⁴Department of Pharmaceutics, M.V.P. Samaj’s College of Pharmacy, Near K.T.H.M. Campus, Gangapur Road, Nashik-422002, Maharashtra, India.

 

ABSTRACT:

The purpose of the present research work was to develop a robust and physicochemically stable pMDI formulation for pulmonary delivery of an Glucocorticoide, drug-Beclomethasone. The pMDI was quickly developed, providing a reliable dose in a robust, convenient and multi-dose preparation. Fortunately, at that time, metering valves capable of developing at least 100 precise spray doses had just become available. Sprays from pMDIs are self-propelled, the pressure of propellants inside the canister being used to force the spray out of the pressure of propellants inside the canister being used to force the spray out of the device via a narrow nozzle in the plastic actuator.Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity. It is extensively hydrolysed via esterase enzymes to the active metabolite beclometasone-17 monopropionate (B-17-MP), which has potent topical anti-inflammatory activity. Formulation contains Anhydrous Beclometasone Dipropionate (Micronised) , Ethanol , Oleic Acid  , HFA 134a(1,1,1,2 Tetrafluoro Ethane), HFA 227ea (1,1,1,2,3,3,3- Heptafluoro Propane) ,  Propylene Glycol , PEG 300, PEG 1000, Povidone K-25. formulation was evaluated  for fine particle dose, mass median aerodynamic diameter, uniformity of dose, leak test, water content, net content, no of doses. Hence it was concluded that pressurised based MDI formulation in an attempt to develop pulmonary administrable product of Beclomethasone was found to be stable and robust with desired attributes of packaging requirements.

 

 

INTRODUCTION:

Until the second half of the 20^th century, hand-held squeeze-bulb nebulisers were used to deliver inhaled drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Asthma is a chronic inflammation of the bronchial tubes (airways) that causes swelling and narrowing (constriction) of the airways. The result is difficulty breathing. Asthma is also a public health problem in developing countries : India has an estimated 15 to 20 million asthmatics²¹.The bronchial narrowing is usually either totally or at least partially reversible with treatments.

 

Chronic obstructive pulmonary disease (COPD) is comprised primarily of three related conditions - chronic bronchitis, chronic Asthma, and Emphysema^1,5. Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity. It is extensively hydrolysed via esterase enzymes to the active metabolite beclometasone-17 monopropionate (B-17-MP), which has potent topical anti-inflammatory activity. Beclometasone dipropionate exerts a topical, anti-inflammatory effect in the lungs and is well established in the prophylactic management of mild, moderate and severe asthma in adults and children. An alternative explanation for this finding is that the oral bioavailability of BDP was also limited by dissolution or absorption rate limited kinetics. And it also happens to be a very poorly water soluble drug.  Hence there was a strong need to look for newer routes of administration. So this work was carried out for delivering the drug locally to the pulmonary by formulating drug solution to be delivered as a pMDI, as solution increases the contact surface and promote drug absorption, improves lung deposition of the drug, provides a targeted delivery of drug and minimizes adverse effects. Nebulisers transform an aqueous product in which drug particles are dissolved or suspended into an aerosol cloud for inhalation by the patient^1,2. The MDI is a pocket-sized, hand-held, pressurised multiple-dose inhalation delivery system. It delivers small, precisely measured therapeutic doses, greatly minimizing the risk of adverse side effects¹⁹.Unlike most nebulisers, it is portable and convenient to use. MDIs can be used for the inhalation of all commonly prescribed respiratory medications for the treatment of asthma and COPD. The MDI gained rapid acceptance among physicians and their patients as a superior means of drug delivery. It has proven safe, effective and reliable for virtually all patients, and is the mainstay of successful asthma therapy worldwide¹⁸.The essential components of an MDI are a storage canister; a medicinal formulation, including at least the propellant and the active ingredient(s); a metering valve to control the discharge of precise doses of formulation; and an actuator². Formulations containing one of 2 hydrofluoroalkanes (tetrafluoroethane [HFA-134a] and heptafluoropropane [HFA-227]) are now appearing on the market.³ Reformulation of pMDIs with HFA propellants has led to many challenges, often involving the development of new excipients and metering valves^4,5.HFA-134a and HFA- 227 have broadly similar thermodynamic properties to CFC-12, but no HFA equivalent to CFC-11 or CFC-114 is available, so excipients with lower volatility may be required to modify the vapour pressure⁶.The lubricant function of surfactant is not required in newly developed valve systems and this has permitted development of commercial beclomethasone dipropionate (BDP) HFA MDIs without inclusion of surfactant⁸.New surfactants that are more soluble in HFA are under investigation. These include polyethylene glycol (PEG), propoxylated PEG and perfluoroalkonic acids but they will not be available until their safety has been demonstrated in chronic respiratory administration¹³.Another approach is to employ a co-solvent to solubilise surfactant in HFA and this may also overcome some of the manufacturing difficulties associated with the absence of a high boiling point replacement for CFC-11¹¹.The concentration of the suspension, method of micronisation and particle size distribution of micronised drug will influence the spray characteristics of the product^9,10,20. A broad range of medications worldwide has been developed for the treatment of asthma, chronic obstructive pulmonary disorder (COPD) and respiratory infection. Already available as HFA-MDI medications are e.g. disodium cromoglycate, nedocromil, reproterol, isoproterol in combination with atropinemethylbromide and dexamethasone, procaterol, salmeterol, salbutamol, beclomethasone, fenoterol, ipratopium bromide, fluticsone, and combination⁷.The essential components of an MDI are a storage canister; a medicinal formulation, including at least the propellant and the active ingredient(s); a metering valve to control the discharge of precise doses of formulation; and an actuator. The storage canister is placed valve-down into the actuator. In press-and-breathe MDIs, the patient pushes down on the canister to release a dose. Breath-actuated MDIs actuate automatically during inspiration. Inside the canister is a complex formulation developed specifically for use in an MDI¹⁷.Reformulation of pMDIs with HFA propellants has led to many challenges, often involving the development of new excipients and metering valves^15,16.

Fig.1. Schematic diagram of typical pressurized metered-dose inhaler²⁰.

 

MATERIAL AND METHODS:

EQUIPMENTS                                                                                                                            

Pressure Mixing vessel  (with Homogeniser) SS. (3L) were purchase from pamasol,  SS Membrane Filtration Assembly (0.2 µ) were purchase from electrolab, Solution Filling m/c  X02039 were purchase from  electrolab, Product Recirculation Multilobe Pump were purchase from pamasol, Crimper X02002-0043 were purchase from pamasol, Weighing Balance 1.2 kg (Accuracy 10 mg) were purchase from  Sartorious, Propellant Filling Pump P2008/12 were purchase from pamasol, Diaphragm Propellant Filler P2079 were purchase from pamasol, ultrasonic (1.5l) was obtained from pci.

 

INGREDIENTS

Anhydrous Beclometasone Dipropionate (Micronised)  were purchase from M/s Symbiotec, Ethanol was obtained from M/s Hayman, Oleic Acid were purchase from M/s Croda , HFA 134a(1,1,1,2 Tetrafluoro Ethane), HFA 227ea (1,1,1,2,3,3,3- Heptafluoro Propane) were purchase from M/s Dupont M/s Ineos, Fluor Propylene Glycol were purchase from manali, PEG 300, PEG 1000, Povidone K-25 were purchase from Croda.

 

MANUFACTURING PROCEDURE FOR PMDI

 

 

Fig.2 Manufacturing procedure for pMDI

 

MANUFACTURING PROCEDURE

1. PROCEDURE FOR DRUG SOLUTION PREPARATION

—  Step-I: Co-Solvent was weighed and filtered through 0.22 µ filter and transfer into mixing vessel.

—  Step-II: It was homogenized at 300-400 RPM

—  Step-III: Weighed Surfactant was added into mixing vessel (Step-I) and stirring was continued for 5 min ±1.

—  Step-IV: API was accurately weighed on weighing scale and transferred into mixing vessel at 600-800 RPM and continue for 20 min ± 2 min.

—  Step-V: After completion of stirring the concentrate weight from display was recorded.

—  Step-VI: The Solution Filling m/c X02039 was set for desired weight 2.03 g (limit 1.97-2.09 g).

 

2. PROCEDURE FOR AEROSOL FILLING

—  Step-I:The above drug solution was filled into canister.

—  Step-II: It was Crimped with 50 mcl metered valve.

—  Step-III: Charged with propellant HFA 134a or 227ea.

 

Qty to be filled per canister

Concentrate: 2.03 g (Limit 1.97 g-2.09g)

Propellant: 11.77 g (Limit 11.6-11.9 g)

Total Net content per canister =13.8 g (Limit 13.6-14.0 g)

Fill initial 5 samples as per the above fill weights and send to QC for analyzing drug content per actuation, moisture content, average shot weight, leak test etc.  

Start filling after QC approval. 

Check the gross weight of individual canister (Limit 21.7-22.5 g) and reject the unit which falls out of range.

 

IN PROCESS CONDITION DURING BATCH MANUFACTURING AND FILLING

1)      Environmental condition:-

a)      Temperature- NMT 25˚c

b)      Humidity- NMT 40 %

2)      Equipment parameter:-

a)      Diaphragm filler- limit 5-6 bar

b)      Filling vaccum- 55-66 mmhg

c)      Propellant pump air pressure- 5-6 bar

d)      Jacket temperature- 10-15˚c

e)      Product temperature- 10-15˚c

f)       Pressure inside canister- 65-75 psi.

 

Packing                                                                                                         

After completion of quarantine period the canisters are then re-weighed to remove the gross leakers.

g)      The canisters are then primed on-line by spraying 2-3 shots to waste under extraction.

h)      The primed canisters are then labelled and actuators 

are attached.
The Labelled canisters are then placed into unit cartons with patient information leaflet.

 

 

DEVELOPMENT: 250 MCG BECLOMETHASONE  PRESSURIZED METER DOSE

Table no.1 Compositions of formulation batches 1-7

Sr.  No.	Ingredients	% Composition
		B.No.1	B. No. 2	B. No. 3	B. No. 4	B. No. 5	B. No. 6	B. No. 7
1	Anhydrous Beclometasone Dipropionate	0.043	0.043	0.043	0.043	0.043	0.043	0.043
2	Ethanol	14	14	14	14	14	14	14
3	Oleic Acid	-	0.015	0.015	0.015	0.015	0.015	0.2
4	Propylene Glycol	-	-	1	-	-	-	-
5	PEG 300	-	-	-	1	-	-	-
6	PEG 1000	-	-	-	-	0.5	1	1
7	Povidone K-25	-	-	-	-	-	-	0.2
8	Propellant HFA 134 a	85.65	85.94	84.94	84.94	85.44	84.94	84.55
9	Propellant HFA 227 ea	-	-	-	-	-	-	-

 

 

Formulation Batches

·      Formulation batches 1 and 2 are based on the comparison of the product characteristics (MMAD and FPD) of formulation without oleic acid and formulation containing oleic acid using 0.3 mm orifice pp adaptor, 20 mm metered valve (50 µm) and 19 cc aluminium anodised canister.

·      Formulation batches 3 and 4 are based on the comparison of the product characteristics (MMAD and FPD) of formulation containing oleic acid and Propylene glycole and formulation containing oleic acid and PEG 300.

·      Formulation batches 5 and 6 are based on the comparison of the product characteristics (MMAD and FPD) of formulation containing oleic acid and PEG 1000 (0.5%) and formulation containing oleic acid and PEG 1000(1%).

·      Formulation batches 7 is based on the product characteristics (MMAD and FPD) of formulation containing oleic acid, ethanol, Povidone-K25 and PEG 1000(1%).

·      All batches are kept in different stability conditions like 30°C/75% RH, 40°C/75%RH and room temperature and observed for physical stability

 

Formulation Batches

·        Batches 8 - 12 are aimed at comparing the product characteristics (MMAD and FPD) of formulation containing Oleic Acid concentrations 0.1%, 0.2%, 0.3%, 0.45% and 0.6% respectively.

·        All batches are kept in different stability conditions like 30°C/75% RH, 40°C/75%RH and room temperature and observed for physical stability.

 

 

Formulation Batches

·        Propellant HFA 134a was replaced by Propellant HFA 227ea into batches 13–15.

·        Batches 13 was conducted without surfactant and was evaluated its MMAD of droplet size by using Propellant HFA 227ea.

·        Batch 14 and 15 was taken with oleic acid concentration of 0.2% and 0.45% to provide physical stability to the formulation.

·        All batches are kept in different stability conditions like 30°C/75% RH, 40°C/75%RH and room temperature and observed for physical stability.

 

Glass Vial Observation:

·        In all batches the formulation (solution) are taken in glass vials and observed for physical stability of the formulation.

·        Visual inspection includes aggregation, discoloration, corrosion and drug adhesion to packing are observed.

·        Glass vial observation is to be carried out at a regular interval of 1, 2, 3, 6, 12, 24 months and kept at quarantine area.Finished product Specification

 

 

BECLOMETHASONE 250 MICROGRAMS PER ACTUATION PRESSURISED INHALATION SOLUTION 

The final selected batch was found to be batch no. 11, as this batch was found to be highly stable as compared to rest of the batches and it shows much better results compared to that of the innovator product.

Table no.2 Compositions of formulation batches 8-12

Sr.  No.	Ingredients	% Composition
		B. No. 8	B. No. 9	B. No. 10	B. No. 11	B. No. 12
1	Anhydrous Beclometasone Dipropionate	0.043	0.043	0.043	0.043	0.043
2	Ethanol	14	14	14	14	14
3	Oleic Acid	0.1	0.2	0.3	0.45	0.6
4	Propylene Glycol	-	-	-	-	-
5	PEG 300	-	-	-	-	-
6	PEG 1000	-	-	-	-	-
7	Povidone K-25	-	-	-	-	-
8	Propellant HFA 134 a	85.85	85.75	85.65	85.50	85.35
9	Propellant HFA 227 ea	-	-	-	-	-

Table no.3 Compositions of formulation batches 13-15

Sr.  No	Ingredients	% Composition
		B.No.13	B. No. 14	B. No. 15
1	Anhydrous Beclometasone Dipropionate	0.043	0.043	0.043
2	Ethanol	14	14	14
3	Oleic Acid	-	0.2	0.45
4	Propylene Glycol	-	-	-
5	PEG 300	-	-	-
6	PEG 1000	-	-	-
7	Povidone K-25	-	-	-
8	Propellant HFA 134 a	-	-	-
9	Propellant HFA 227 ea	85.65	85.75	85.50

 

Table no.4 Finished product Specification

Sr. No.	Tests	Specifications	Results
01	Description	An Aerosol solution filled in an Anodized Aluminum Canister fitted with metered valve provided with oral inhalation actuator.	Complies
02	Assay	80 - 120 %	3 Month-100.9
03	Fine Particle Dose (FPD)	Below 5.8 µm and  NLT  20 mcg	3 Month-74.90 mcg
04	Emitted dose	NLT  35%	3 Month-53.7%
05	Mass Median Aerodynamic Diameter (MMAD)	NLT  2 µm	3 Month-1.9981µm
06	Uniformity of Delivered Dose  (UODD)	Limit 75-135%	3 Month- 90.5%
07	Water content	NMT  2500  ppm	3 Month-1823.5ppm
08	No. of Doses	NLT 200 nos.	3 Month- 239
09	Net Content	13.6-14.0 g	3 Month- 13.9 g
10	Leak Test	NMT 3.5%/year	0.339%

 

CONCLUSION

The purpose of the present research work was to develop a robust and physicochemically stable pMDI formulation for pulmonary delivery of an Glucocorticoide, drug-Beclomethasone.From the literature review, it was found that the absence of detectable concentrations of BDP in the plasma following oral administration is predictable from its very high clearance, which would be expected to result in a high first pass metabolism. Therefore targeting Beclomethasone as pMDI form as spray formulation for the management of Asthma and COPD is a rationale approach.

Beclomethasone was formulated by pressure filling technique as MDI formulation. Different approaches were practiced to make a stable dosage form which can be delivered into the lungs. Beclomethasone pMDI 250 mcg was evaluated. Hence it was concluded that pressurised based MDI formulation in an attempt to develop pulmonary administrable product of Beclomethasone was found to be stable and robust with desired attributes of packaging requirements. 

 

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19     Jay Grossman, "The Evolution of Inhaler Technology," 31 J. Asthma 55,57-58 (1994)

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21     Statement by Dr. Nikoli Khaltaev, World Health Organization Expert (7 Dec. 1998 Press Release).

 

 

 

 

Received on 15.06.2014                Modified on 25.06.2014

Accepted on 02.07.2014                © RJPT All right reserved