Advances In Dry Powder Inhaler Development Biology Essay

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Local delivery of medication to the lung is highly desirable as the principal advantages include reduced systemic side effects and higher dose levels of the applicable medication at the site of drug action. This administration could be particularly useful for patients with specifically chronic pulmonary infections or pulmonary diseases, such as cystic fibrosis, asthma or lung cancer. Dry powder inhaler (DPI) systems are widely accepted as an alternative to injection and oral administration for pulmonary delivery. In parallel to expansion of the DPI in the market, the engineering science of DPI formulations and devices have also grown. In this review, we present information regarding some recent advances DPI development. A number of clinical trials reports along with potential clinical finding are discussed in this review. Most of the new DPI development includes combination molecules.

Keywords: Pulmonary drug delivery, Dry power inhaler, Asthma, COPD, Clinical trials.

Introduction

In recent years, increased interest in the scientific basis of respiratory therapy has given rise to a growth in technology that makes use of the inherent advantages of the inhaled route of drug administration for the treatment of both pulmonary (Asthma, COPD) and non-pulmonary (e.g. Parkinson) diseases. A key advantage of this route is that it enables delivery of low doses of an aerosolised drug to its site of action for a local action, which leads to a rapid clinical response with few systemic side-effects, particularly for aerosolized ?-agonist therapy.1 Drug delivery to the systemic circulation via the distal lung results in rapid absorption of the drug from this large surface area. However, when inhaled drugs are administered for effects on the airway (eg, inhaled corticosteroids), systemic absorption of the drug can give rise to unwanted side-effects.

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The three main delivery systems used for aerosol inhalation in humans are pressurized metered-dose inhalers (MDI), nebulizers, and dry powder inhalers (DPI). DPIs appear to be the most promising of these for future use because the device is small and relatively inexpensive, no propellants are used, and breath actuation can be used successfully by many patients with poor MDI techniques. In this review we have focused our discussion of novel DPI formulations which are approved in the last few years or are under clinical development. Most of the new formulations are combination therapy based. A number of new medicines are in phase 2/3 from pharma majors like GSK, Novartis etc while small CROs and Pharmaceutical organization are in developing stages. Multinational clinical trials are seemed to be successful in the next years as per the existing clinical outcome [1].

The common respiratory disease includes Asthma, Chronic obstructive pulmonary disease (COPD) and Cystic fibrosis (CF) etc. Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm.[2] Common asthma symptoms include wheezing, coughing, chest tightness, and dyspnea.[3] Asthma is thought to be caused by a combination of genetic and environmental factors.[4] Its diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry.[5] It is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate.[6] COPD also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD), is the occurrence of chronic bronchitis or emphysema, in which airways get narrower overtime. This results in airflow obstruction in lungs, leading to shortness of breath. In clinical setting, COPD is defined by low airflow on lung function tests [2]. Cystic fibrosis (CF) (mucoviscidosis) is an autosomal recessive genetic disorder that affects most critically the lungs, and also the pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions.[1]

In the present review we have address the most recent development in DPI. The clinical study along with their significant findings is also discussed (Table 1).

UMEC/VI

UMEC/VI (ANORO ELLIPTA�) was accepted by in Feb 2013 as New Drug Application (NDA) submission. In Europe MAA has been validated. ANORO ELLIPTA� is combination of 2 investigational bronchodilator molecules - GSK573719 or umeclidinium bromide (UMEC), a long-acting muscarinic antagonist (LAMA) and vilanterol (VI), a long-acting beta2 agonist (LABA), administered using the ELLIPTA� inhaler. UMEC/VI is one of pipelined project in the GSK respiratory which includes fluticasone furoate/vilanterol (FF/VI, RELVAR� and BREO�), VI monotherapy and MABA (GSK961081), developed in collaboration with Theravance, as well as GSK�s investigational medicines FF monotherapy, UMEC monotherapy and anti-IL5 MAb (mepolizumab). ANORO�, RELVAR�, BREO� and ELLIPTA� are trademarks of the GSK [8, 9].

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Clinical trials were conducted to evaluate the efficacy and safety of GSK573719/GW642444 and the individual components delivered once-daily via a novel dry powder inhaler (nDPI) in subjects with COPD. Treatment with UMEC/VI 125/25 mcg, UMEC 125 mcg, and VI 25 mcg resulted in statistically significant improvements in the primary efficacy endpoint (PEE) of trough FEV1 at day 169 compared with placebo [10-12].

In another phase 3 study, subjects were randomized in a 3:3:3:2 ratio to UMEC/VI, UMEC, VI and placebo for 24 weeks. Treatment with UMEC/VI 62.5/25 mcg, UMEC 62.5 mcg, and VI 25 mcg resulted in statistically significant improvements in the (PEE) of trough FEV1 at 169th day compared to placebo [13].

A multicenter clinical trial was conducted to compare the efficacy and safety of GSK573719/GW642444 with GSK573719 and with tiotropium (TIO) over 169 days in subjects with COPD. Treatment with once-daily UMEC/VI 125/25 resulted in a statistically significant improvement in lung function as measured by the primary endpoint (PE), trough FEV1 at in 24th week as compared to TIO. The comparison of UMEC/VI 125/25 and UMEC 125 with respect to the PE was not statistically significant. On the other hand treatment with UMEC/VI 62/5/25 did not show statistically significant improvements in the PE compared with UMEC 125 [14-17] (Table 2, 3).

Tudorza Pressair

Tudorza Pressair (aclidinium bromide inhalation powder) 400mcg is an anticholinergic for the long-term, maintenance treatment of bronchospasm associated with COPD. Inhalation delivery of Tudorza achieved bronchodilation by suppressing the muscarinic M3 receptor. Tudorza is administered using a multiple-dose DPI, Pressair, which delivers 60 doses of aclidinium bromide [18] (Fig 1).

Tudorza Pressair (TP) was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo controlled trials in patients with COPD. In these trials, 636 patients were treated with TP at the recommended dose of 400 mcg twice daily. Trial A included TP doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol as active control, and placebo. This study showed the effect on trough FEV1 and serial FEV1in patients treated with the TP 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the 400 mcg twice daily dose [19] (Fig 2).

Confirmatory trials

The clinical trials B, C, and D were 3 randomized, double-blind, placebo-controlled trials in patients with COPD. Trials B and C were 3 months in duration, while Trial D was 6 months in duration. These trials enrolled 1,276 patients with COPD. Serial spirometric evaluations were performed in the 3 trials. Results for the other two placebo controlled trials were similar to the results for Trial B. Mean peak improvements in FEV1, for TP relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were found to be similar at week 12. (Fig 3)

On July, 2012, Almirall was granted European Commission marketing approval for Eklira/Bretaris Genuair�(aclidinium 322 mcg twice daily) in all EU member states, plus Iceland and Norway. Clinical efficacy studies showed that aclidinium provides significant and sustained bronchodilation from the 1st dose (within half hour). Reduction in moderate and severe exacerbations by approximately 30% was observed. In addition the studies demonstrated that aclidinium provided clinically meaningful improvements in breathlessness (assessed using the Transition Dyspnoea Index [TDI] [20] and disease-specific health status (assessed using the St. George�s Respiratory Questionnaire [SGRQ] [21].

In the six month study, patients receiving Aclidinium 322 mcg twice daily experienced an improvement in FEV1. Significant bronchodilatory effects were observed from day one and were maintained over the six month treatment period. Almost similar observations were found with Aclidinium in the 3 month study. Aclidinium demonstrated clinically improvements in breathlessness assessed by TDI mean changes vs baseline =1 unit (p<0.001) and disease-specific health status assessed using SGRQ: mean change vs baseline -4.6 units (p<0.0001). It was observed that patients treated with aclidinium required less rescue medication than those treated with placebo (a reduction of 0.95 puffs per day at 6 months [p=0.005]). Aclidinium reported to improve daily symptoms of COPD and night-time and early morning symptoms. The pooled efficacy analysis (6-month and 3-month placebo controlled) revealed a statistically significant reduction in the moderate to severe exacerbations rate, with aclidinium 322 mcg twice daily compared to placebo (Table 3) [22-26].

Inavir �

Inavir is an influenza antiviral product (laninamivir octanoate hydrate) for dry powder inhalation developed by Daiichi Sankyo Company, Limited. Inavir was found to significantly reduce the incidence of influenza infection compared to placebo in a phase 3 clinical study. In an efficacy study, Inavir was investigated to prevent influenza virus infection of patients with infection from influenza A or B virus. Inavir� statistically significantly reduced the incidence of the clinical influenza virus infection among household contacts, the primary endpoint of efficacy, demonstrating its protective efficacy (Fig 4) [27-30].

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Colobreathe dry powder

On Feb 12, Forest Laboratories was granted EMA approval to market Colobreathe DPI colistimethate sodium for inhalation for treating CF patients aged 6 years and older with chronic lung infection caused by P. aeruginosa. The pivotal study which was submitted to EMA for approval was an open-label active comparator clinical study to compare the efficacy of Colobreathe to TOBI� (tobramycin nebuliser solution for inhalation). The clinical data from the pivotal study of Colobreathe showed that overall better tolerability and no emergence of antibacterial resistance. In a phase 3 study (TRIAL REG NO: Eudra CT 2004-003675-36.) Patients with stable CF aged ?6 years with chronic P aeruginosa lung infection were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). The duration of study was 24 weeks. 380 patients were randomised. The change in (FEV(1)% predicted) at week 24 was -0.98% in the intention-to-treat population and -0.56% in the per protocol population. Colistin-resistant isolates in both groups was ?1.1%. CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin [31,32].

QVA149

QVA149 (indacaterol 110 /glycopyrronium bromide 50 mcg) is an investigational inhaled, once-daily, fixed dose combination of the long acting beta2-agonist (LABA) indacaterol, and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (NVA237).QVA149 is being investigated for the maintenance treatment of COPD in the Phase III IGNITE clinical trial program. Clinical data from the Novartis once-daily COPD clinical trial programs were presented at the ERS Congress. Overall, Novartis presented 14 abstracts, including data from the investigational QVA149, IGNITE program, the glycopyrronium bromide (Seebri� Breezhaler�) GLOW Phase III clinical trial program and the indacaterol maleate (Onbrez� Breezhaler�) INERGIZE Phase III/IV clinical trial program (Table 5) [33,34].

QVA149 responded superior bronchodilation compared to indacaterol 150 mcg, glycopyrronium 50 mcg, salmeterol/fluticasone 50/500 mcg BID, OL tiotropium 18 mcg and placebo [33,34] Seebri� Breezhaler� (glycopyrronium bromide) demonstrated rapid, sustained bronchodilation and reduced exacerbations similar to OL tiotropium 18 mcg in GLOW pooled data analysis [35,36] Onbrez� Breezhaler� (indacaterol maleate) was superior to OL tiotropium 18 mcg in improving severe breathlessness symptoms in pooled INERGIZE data [37].

Study designs

SHINE was a 26 week placebo and active controlled pivotal trial of 144 patients with moderate-to-severe COPD to assess efficacy in terms of trough FEV1[1]. ILLUMINATE assessed the efficacy, safety and tolerability of QVA149 compared to twice-daily fixed dose combination of salmeterol/fluticasone 50/500 mcg in COPD patients [2]. ENLIGHTEN was a 52 week pivotal trial of 339 COPD patients designed to assess the safety and tolerability [6]. GLOW1 was a 26 week study of glycopyrronium 50 mcg or placebo. GLOW2 was a 52 week comparative study of glycopyrronium 50 mcg or placebo, and included an exploratory arm to compare the effects of once-daily OL tiotropium 18 mcg versus placebo [35,36].

The investigational QVA149 IGNITE phase III clinical studies (SHINE, ILLUMINATE and ENLIGHTEN) showed that QVA149 significantly improved lung function compared to other COPD therapies [33, 34, 37]. Data from the GLOW program showed that glycopyrronium 50 mcg once daily responded rapid and sustained bronchodilation, and reduced exacerbations and symptoms in comparison to placebo, similar to the levels observed with open-label (OL) tiotropium 18 mcg. Pooled-analysis from the INERGIZE studies demonstrated that Onbrez� Breezhaler� 300 mcg was superior to OL tiotropium 18 mcg in improving breathlessness in COPD patients who had more severe breathlessness symptoms on entry to the studies (p<0.05)[38-54].

QAT 370

QAT 370 is an investigational compound of Novartis, it is under phase 3. The molecule is having antimuscarinic property. In Germany at 3 centres a multi-centre clinical study was conducted to assess the safety and tolerability of an efficacious dose of QAT370 or matched placebo compared to open-label tiotropium bromide in mild-to-moderate COPD patients.

The study consisted of a randomized 3 way crossover design with QAT370, QAT370 matched placebo and tiotropium administered across three treatment periods within each of 6 treatment sequences. The dose of the investigational drug (QAT370) was 400 ?g or matching placebo. The dose of tiotropium was 18 ?g (the recommended single daily dose).

QAT370 400 ?g significantly increased the FEV1 AUC 0-24h on Day 7 by 24% relative to placebo, and the increase by Tiotropium was 16% when compared to placebo. The effect on FEV1 at trough, i.e. FEV1 AUC 23-24h, was also statistically significant but slightly lower in magnitude. The mean FEV1 improvement over placebo ranged between 10% and 24% on Day 7 and was statistically significant at all times. The overall comparison of QAT370 to placebo (averaging over all time points) was significant for FEV1 but did not reach statistical significance for Inspiratory Capacity, although it showed a positive trend at all time points examined which is consistent with AUC 0-24h results.

TOBI Podhaler

TOBI Podhaler 28 mg Tobramycin, DPI comes as hard capsules. TOBI Podhaler is indicated for the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged 6 years and older with CF. Phase III trial consisted of 2 studies and 612 treated patients having CF. In the multicentre placebo controlled, study, TOBI Podhaler significantly improved lung function compared to placebo. The product is development of Novartis (Fig 5).

Spiriva� HandiHaler� (tiotropium bromide inhalation powder)

Spiriva� HandiHaler� is DPI formulation of tiotropium bromide, a product of Boehringer Ingelheim International GmbH. The clinical study revealed that the mean difference in change of isotime inspiratory capacity PE or the total normal exhaled air, from baseline to week 6 during rest and exercise between SPIRIVA and placebo was statistically significant in patients with GOLD 1 and 2. The difference in change from baseline to week 6 in exercise duration between SPIRIVA and placebo (secondary endpoint) was not statistically significant in the combined GOLD 1 and 2 groups or the GOLD 1 patient subgroup. The clinical study included 126 current /former smokers age 40 or older with a post-bronchodilator FEV1/FVC less than 70 percent and a FEV1 greater than or equal to 50 percent predicted airflow limitation [57-61] (Fig 6).

AeroVanc

AeroVanc, (Savara Pharmaceuticals) a DPI formulation of vancomycin, is the first inhaled antibiotic being developed for the treatment of respiratory methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with CF. When given by parenteral delivery Vancomycin is choice for the treatment of MRSA-related bronchopneumonia, however, parenteral administration, causes poor penetration into the lungs and systemic toxicities limit its use in a chronic setting. AeroVanc is the first inhaled antibiotic being developed for the treatment of MRSA infection in cystic fibrosis patients. AeroVanc is supposed to improve clinical efficacy and reduce side effects due to systemic drug exposure, when given by inhalation route at the site of infection. The phase 1 study in healthy and CF patients demonstrated positive safety and tolerability results, as a once- or twice-daily treatment for pulmonary MRSA infections. vancomycin concentration in sputum was found effective to kill MRSA. The Phase IIa study was planned in MRSA-infected patients. Savara Pharmaceuticals' vancomycin, first inhaled antibiotic DPI formulation designated by USFDA as orphan drug, for the treatment of pulmonary MRSA (62-64) (Fig 7).

iSPERSE

iSPERSE (by Pulmatrix) dry powders comprise proprietary cationic salt formulations developed for oral inhalation having unique small particle size, high density and high dispersibility. These properties make iSPERSE suitable to deliver macromolecules like proteins and peptides. Additionally, iSPERSE�s proprietary powders allow for flexible formulation with straightforward manufacturing, supporting the formulation of small and large molecule drugs as well drug combinations, including triple drug combinations [65,66].

Easyhaler�

Easyhaler�, an in-house developed dry-powder inhaler. Orion has developed Easyhaler-adapted DPI of several generics (e.g. salbutamol, beclometasone, budesonide, formoterol) used in the treatment of asthma and COPD. At the moment under development are new combined formulations of budesonide formoterol, and fluticasone-salmeterol for the treatment of asthma and COPD [67] (Fig 8).

R343

R343 is an inhaled SYK inhibitor that is being evaluated as a potential treatment for allergic asthma, developed by Rigel Pharmaceuticals, Inc. A phase 2 study of R343, was designed in 270 adults with allergic asthma called SITAR (SYK Inhibition for Treatment of Asthma with R343), for 8 weeks of treatment with either of two different doses of the study agent or placebo. The PE of study will be the measurement of each patient's change in FEV1 from baseline to dosing completion. Rigel will be using the 3M� Taper DPI device for this trial. Rigel expects to complete this study in 2013 [68,69].

CVT-301

Civitas Therapeutics, Inc., is developing transformative therapeutics using the ARCUS � respiratory delivery platform. Which is currently under phase 2a clinical trial in Parkinson�s patients evaluating CVT-301, an inhaled formulation of levodopa (L-dopa), for the rapid relief from motor fluctuations. CVT-301 provides immediate onset of a large and precise dose of L-dopa. ARCUS � is a clinically proven dry powder pulmonary delivery platform of Civitas [70-72].

GSK-573719

GSK-573719 is a muscarinic receptor antagonist developed for once-daily treatment of COPD by GSK. Clinical study evaluated safety and tolerability of GSK-573719 at different doses (100, 500 and 1,000 mg) in healthy volunteers [73]. A second trial evaluated the safety, tolerability, pharmacodynamics and pharmacokinetics of single doses (750 and 1,000 mg) and repeat doses over 2 weeks (250�1,000 mg once daily) in healthy male and female subjects [74]. A placebo-controlled study evaluated the safety, tolerability, pharmacodynamics and pharmacokinetics of single inhaled doses of GSK-573719 and tiotropium bromide (18 mg) via DPI in COPD patients [75]. But no significant results were observed with this molecule.

Milveterol

Milveterol (GSK-159797; TD-3327) is a once-daily LABA under development by GSK and Theravance. In clinical study milveterol achieved increase in FEV1 throughout the 25-h evaluation period in a study of 38 patients with mild asthma following single-dose inhalation. In placebo-controlled study the bronchodilatory effect, safety and tolerability of milveterol was evaluated by administering via a dry-powder inhaler in 20 patients with mild asthma [76]. A clinically significant increase in FEV1 over 24 h, was observed. At 24 h, 10- and 20-mg doses of milveterol responded adjusted mean changes from baseline FEV1 of 460 and 540 mL, respectively, compared to a change of 130 mL for placebo. In asthma patients, all doses of milveterol (10, 15 and 20 mg), once daily, produced comparable bronchodilatory effect to 50 mg salmeterol, dosed twice daily, at trough on the fourteenth day of treatment [77].

Other molecules

QMF149 is combination of Novartis�s experimental beta2-agonist indacaterol with Schering-Plough's inhaled corticosteroid mometasone furoate. It is under phase II study. Novartis�s concept device Twisthaler� is supposed to be used for these combination drugs (Table 6)[78-81].

Some molecules are under development at phase I e.g. QBX258, QAB149B at Novartis. A DPI formulation of ciprofloxacin by Novartis is also in Phase II study, but has not yet been reported Clinical study compared two doses (32.5 and 48.75 mg) of ciprofloxacin against placebo. No statistically significant difference in FEV1 (the primary endpoint) was found after 28 days of therapy when comparing either dose with its matching placebo [82].

Mannitol is also under phase III study (CF301) as DPI formulation. In a comparative study with placebo in 235 patients statistically significant result in FEV1 were observed. Another Phase III study (CF302) reported a 54-mL increase in FEV1 after 26 weeks. Data from both trials demonstrated that mannitol does in fact improve FEV1 in the order of 50 -100 ml [83].

Conclusions

In the past 5 years, several innovative developments in the area of respiratory delivery have advanced the field of dry powder inhaler design. Bronchodilators remain as heart for asthma and COPD maintenance therapy. Most of the new molecules have shown promising results in phase II/III. Interest towards tiotropium is going on as it has shown comparable effect to bronchodilators. The current clinical trials focus on combination therapy. Beside formulation development it is very challenging to warrant clinical potential of new drugs and to meet regulatory expectations. For product coming up with new device the device functionality concern needs to be overcome by the innovators. Although the old and existing asthma/COPD drug is well placed in market but there is always a need for improvement in terms of medical needs from patient view and new market opportunity for business point of view. For example Salmeterol is supposed to be replaced by Vilanterol. Vilanterol had a significantly longer duration of action compared to salmeterol as vilanterol still responded a better significant bronchodilator action. The first patent for formoterol and salmeterol (first patent in 2008) has expired. New generics are not in the US/EU but available in ROW market. The market of single therapy may be replaced by once-daily dual-action ultra-LABA/LAMA combination products.