1. Overview of Pulmonary Drug Delivery

With a deeper understanding of some respiratory diseases, such as asthma, emphysema, chronic bronchitis and chronic obstructive pulmonary disease (COPD), the people have realized that these diseases are of long treatment period, difficult to cure and need long-term medication, and pulmonary drug delivery is a relatively simple and effective way to treat them. Pulmonary drug delivery system refers to a drug delivery system that directly enters the respiratory tract through a special drug delivery device for the topical or systemic treatment. It is widely accepted that pulmonary drug delivery is not only an effective treatment for topical lung diseases (asthma, COPD, bronchiectasis, lung infections, etc.), but also a commonly used treatment to achieve systemic efficacy. The drugs reach the lungs directly after they’re inhaled, which can significantly reduce the drug dosages and thus side effects compared with oral delivery.

The uniqueness of lung anatomy and physiology is one of the major determinants of inhaled drugs. Capillaries are abundant in the lungs. 80% of the pulmonary alveoli are wrapped with capillaries. With a large blood flow of blood vessels, the drugs enter directly into the bloodstream without first-pass effect after they’re absorbed through the blood vessels of the lungs. Therefore, the absorption is very rapid with pulmonary drug delivery. The biometabolic enzymes of the lungs are concentrated in typeⅡpulmonary alveoli cells, which can reduce the hydrolysis of proteins and peptides to some extent once they enter into the lungs, and then ensure the bioavailability of the drugs to deliver efficacy. Currently pulmonary drug delivery has been recommended as the optimal route of administration in many countries to treat respiratory diseases such as asthma and COPD, and is also being used for systemic drugs such as insulin, vaccines and growth hormone.

At present pulmonary drug delivery systems are basically divided into three types, metered-dose inhaler (MDI), nebulizer, powder inhaler or dry powder inhaler (DPI). MDI delivers drugs powered by a propellant called Freon, which destroys the ozone layer in the atmosphere. MDI requires coordination of patients’ inhalation and inhaler actuation. Owing to its bulky device, nebulizer is not portable. Moreover, nebulizer is of low drug delivery efficiency, low performance in repeatability, significant individual difference and long-time drug delivery.

Compared with MDI and nebulizer, the drug powders in DPI are released by the force of the patient’s inspiratory flow. DPI does not require coordination of patients’ inhalation and inhaler actuation, or a propellant, which solves the environmental concerns. Moreover, DPI can deliver larger drug dosages in the form of solid powder and thus can be employed for delivering macromolecules such as protein and peptides, which extends the applied range of pulmonary drug delivery. DPI has grown rapidly in recent years. With people’s enhanced awareness of environmental protection, owing to its advantages of efficient drug delivery, good drug stability and free from the propellant to avoid its destruction of the ozone layer in the atmosphere, DPI has gradually become a new favorite of market and accepted by the patients. More and more pharmaceutical enterprises set foot on it.

2. Overview of Dry Powder Inhaler

Dry powder inhaler (DPI), also known as powder inhaler, refers to the solid drug powders alone or mixed with appropriate carrier, in the form of capsules, vesicles or multi-dose storage, inhaled by the patient with the use of special dry powder inhaler device for a successful pulmonary delivery. It has been studied abroad for decades, and most of the drugs on the market are for the treatment of asthma and COPD.

Some well-known foreign pharmaceutical enterprises have developed their own flagship products, for instance, Sembicobul from Astrazeneca and Serevir from GlaxoSmithKline. Some enterprises even have attempted to challenge the fields of vaccines and protein drugs. Owing to its difficulty of device design, production process and high research cost, research on DPI in China is still in its early stage, and very few DPIs are approved.

Based on Menet database, DPI’s market share in the chemical drug end market of public medical institutions in China has increased from 1.52% in 2013 to 2.08% in 2018, and the sales volume has exceeded CNY 20 billion. Therefore, DPI has a great market prospect in China. Owing to its properties of convenient usage, eco-friendly, free from the propellant, efficient drug delivery, good drug stability, non-invasive drug delivery, less excipients, high drug loading and high level of stability, DPI stands out among various dosage forms and attracts flocks of domestic pharmaceutical scholars for research.

An ideal DPI meets following requirements. (1) Convenient usage and high portability. (2) Easy to inhale. (3) Accurate drug dosages. (4) Utilized for adjustment within a wide dosage range and personalized treatment. (5) Reduce the adsorption and residuals of drugs in the device. (6) Ensure the drug stability in the device. (7) The counting device can display the remaining dosages, without the overdosage danger. (8) Inexpensive.

3. Overview of Dry-Powder Inhalation Capsules

The inhaler device is the core of DPI design, generating turbulent airflow and atomization for the drug delivery, which directly affects the efficacy. Based on the energy source of drug delivery and principle of dosage measure, DPIs are basically divided into three types. (1) Unit-dose DPI (capsule-based), with a simple structure, low internal resistance and accurate dosages. (2) Multiple unit-dose DPI, convenient usage of adjusting the dosages, but with the issues of accuracy, homogeneity of the divided dose and drug stability in the storage unit. (3) Use active inhalation technology with extra energy supply to dispense and deliver drugs, but with the disadvantages of bulky device, inconvenient usage and expensive.

Unit-dose DPI is usually capsule-based, in which an individual dose is contained in an empty capsule and then the contents are inhaled after the puncturing of the capsule by the inhaler device or the separation of capsule cap and body. Due to the special properties of DPI dose, content separation and drug administration process, there’re requirements on the empty capsules that the content powder absorbed by the empty capsules is less than 5%, non-brittle, and the cap body is generally transparent. The empty gelatin capsules and HPMC capsules are two types of capsules that are mainly used. Owing to their features of low activity (high self-stability and low risk of compatibility with packaging materials), low water content and low static, vacant HPMC capsules are more suitable.

4. Advantages of H-caps®-DPI from Lefancaps®

H-caps®-DPI developed by Lefancaps® are hypromellose capsules designed for use with capsule-based dry powder inhalers. According to the properties and quality requirements of dry powder inhalers, H-caps®-DPI have the following advantages.

(1) Low residual powder rate, avoid the content residuals. To control the residual powder rate of dry-powder inhalation capsules to satisfy the needs of the user’s indicators based on their specific delivery dosage requirement.

(2) Good puncturing performance, less likely to produce fragments. The inhaler device punctures the capsule in the actual use of capsule-based dry powder inhaler. In the process of puncturing, no fragments fall off to prevent them from being inhaled into the body.

(3) Small weight deviation, meet the requirements of low-dose drug filling. Normally the loading volume of dry powder inhalers is low with fewer active ingredients, so the filling volume needs to be strictly controlled. When a regular pharmaceutical enterprise does the online control, the weight of capsule shell and the contents are weighed. In this case, the weight deviation of the capsule shell may have an impact on the actual filling volume. Hence, the weight deviation of the dry-powder inhalation capsules needs to be controlled according to the user’s requirements.

(4) Strict microbial index. Based on Ch.P 2020, Volume IV, General Rules 1107, Microbiological Limit Standard for non-sterile drugs, the microbial limit standard for respiratory inhaled drugs is as follows. Total aerobic bacteria ≤ 100CFU /g. Total yeast & mould count ≤ 100CFU /g. Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Cholestate-resistant gram-negative bacteria cannot be detected.

5. Residual Powder and Puncturing Test of H-caps®-DPI from Lefancaps®

5.1 Residual Powder Test: H-caps®-DPI versus RegularVacant Hypromellose Capsules

Figure 1: Residual Powder of H-caps®-DPI (left) versus RegularVacant Hypromellose Capsules (right)

The residual powder test is carried out for H-caps®-DPI and regularvacant hypromellose capsules. The result is shown in Figure 1 that H-caps®-DPI leave less lactose residues with a lower residual powder rate.

5.2 Puncturing Test of H-caps®-DPI

Figure 2: Puncturing Test of H-caps®-DPI, Image 1

Figure 3: Puncturing Test of H-caps®-DPI, Image 2

The puncturing test of H-caps®-DPI is conducted and taken pictures by imaging device as shown in Figure 2 and Figure 3. H-caps®-DPI after puncturing are with a smooth break, and no fragments fall off.

6. Future Prospects of Dry-Powder Inhalation Capsules

With the deterioration of air quality in recent years, the incidence rate of respiratory diseases such as asthma and COPD in China will be further increased in the next few years, which will bring serious challenges to the quality of people’s life. Currently the research on dry powder inhalants in China is still in the imitation stage, and we still lag behind in the quality study methods and indicators. However, dry powder inhalants have a broad market prospect, based on the clinical demand for non-injectable delivery of biological agents such as peptides and vaccines and the development demand of compound preparations. With the continuous growth of dry powder inhalants and novel inhalants in the future, the market demand of dry-powder inhalation capsules will also grow with a promising prospect.

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