PMID- 28593514
OWN - NLM
STAT- MEDLINE
DCOM- 20180517
LR  - 20181113
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 19
IP  - 5
DP  - 2017 Sep
TI  - Influence of Formulation Factors on the Aerosol Performance of Suspension and 
      Solution Metered Dose Inhalers: A Systematic Approach.
PG  - 1396-1410
LID - 10.1208/s12248-017-0095-3 [doi]
AB  - Metered dose inhalers (MDIs) are complex drug-device combination products widely 
      used to treat pulmonary disorders. The efficacy, driven by aerosol performance of 
      the products, depends on a multitude of factors including, but not limited to, 
      the physicochemical properties of drug and nature and amount of excipient(s). 
      Under the quality by design (QbD) paradigm, systematic investigations are 
      necessary to understand how changes in critical quality attributes (CQAs) of 
      formulation, device, and manufacturing process influence key product performance 
      parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose 
      of this work is to provide a better understanding of the effects of different 
      levels of excipients and drug particle size distribution on the aerosol 
      performance of MDI products, while using two fundamentally different MDI products 
      as relevant model systems, Proventil(R) HFA (albuterol sulfate suspension) and 
      Qvar(R) (beclomethasone dipropionate solution). These MDI products, as model 
      systems, provided mid-points around which a design of experiments (DOE), 
      consisting of 22 suspension and 9 solution MDI formulations, were defined and 
      manufactured. The DOE included formulations factors with varying ethanol (2 to 
      20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic 
      acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and 
      solution, respectively) and drug volumetric median particle size distribution 
      (PSD D(50), 1.4 to 2.5 mum for the suspension). The MDI formulations were analyzed 
      using compendial methods to elucidate the effect of these formulation variables 
      (ethanol, oleic acid, and PSD D(50)) on DD and FPD. The outcomes of this study 
      allowed defining design spaces for the formulation factors, such that DD and FPD 
      would remain within specific pre-defined requirements. The systematic approach 
      utilized in this work can contribute as a QbD tool to evaluate the extent to 
      which the formulation factors govern the aerosol performance of MDI drug 
      products, helping to design MDI formulations with desired product performance 
      parameters.
FAU - Sheth, Poonam
AU  - Sheth P
AUID- ORCID: 0000-0001-7101-6665
AD  - Recipharm, 511 Davis Drive, Suite 100, Morrisville, North Carolina, 27560, USA. 
      poonam.aliyah.sheth@recipharm.com.
AD  - Cirrus Pharmaceuticals, Inc., Morrisville, North Carolina, USA. 
      poonam.aliyah.sheth@recipharm.com.
FAU - Sandell, Dennis
AU  - Sandell D
AD  - S5 Consulting, Ekvagen 8, Blentarp, Sweden.
FAU - Conti, Denise S
AU  - Conti DS
AD  - Office of Research and Standards, Office of Generic Drugs, Center for Drug 
      Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 
      USA.
FAU - Holt, Jay T
AU  - Holt JT
AD  - Cirrus Pharmaceuticals, Inc., Morrisville, North Carolina, USA.
AD  - Aurobindo Pharma USA, Inc., Durham, North Carolina, USA.
FAU - Hickey, Anthony J
AU  - Hickey AJ
AD  - Cirrus Pharmaceuticals, Inc., Morrisville, North Carolina, USA.
AD  - RTI International, Research Triangle Park, North Carolina, USA.
FAU - Saluja, Bhawana
AU  - Saluja B
AD  - Office of Research and Standards, Office of Generic Drugs, Center for Drug 
      Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 
      USA.
AD  - Office of Clinical Pharmacology, Office of Translational Sciences, Center for 
      Drug Evaluation and Research, Food and Drug Administration, Silver Spring, 
      Maryland, USA.
LA  - eng
GR  - U01 FD004943/FD/FDA HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20170607
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Aerosols)
RN  - 0 (Solutions)
RN  - 0 (Suspensions)
SB  - IM
MH  - Aerosols
MH  - Chemistry, Pharmaceutical
MH  - *Metered Dose Inhalers
MH  - Particle Size
MH  - Solutions
MH  - Suspensions
OTO - NOTNLM
OT  - albuterol sulfate
OT  - beclomethasone dipropionate
OT  - delivered dose
OT  - design of experiments
OT  - design spaces
OT  - excipients
OT  - fine particle dose
OT  - mathematical models
OT  - metered dose inhalers
EDAT- 2017/06/09 06:00
MHDA- 2018/05/18 06:00
CRDT- 2017/06/09 06:00
PHST- 2017/02/10 00:00 [received]
PHST- 2017/05/01 00:00 [accepted]
PHST- 2017/06/09 06:00 [pubmed]
PHST- 2018/05/18 06:00 [medline]
PHST- 2017/06/09 06:00 [entrez]
AID - 10.1208/s12248-017-0095-3 [pii]
AID - 10.1208/s12248-017-0095-3 [doi]
PST - ppublish
SO  - AAPS J. 2017 Sep;19(5):1396-1410. doi: 10.1208/s12248-017-0095-3. Epub 2017 Jun 
      7.