INTRODUCTION:

Chronic obstructive pulmonary disease (COPD) is a major global health problem with an increasing burden of disease and impact on health care expenditure. COPD is an irreversible airflow limitation. Current conventional treatments aim to relieve symptoms, prevent recurrent exacerbations, maintain optimal lung function and improve quality of life¹.

According to World Health Statistics, COPD will be the third leading cause of death in the world in 2030. Based on data obtained from Basic Health Research (2013), COPD has a prevalence of 3.7% per million population in Indonesia². COPD is like a time bomb in Indonesia, because many people have a very high risk of COPD with impaired lung function but are not yet aware of it^3,4. COPD is a chronic disease that requires long-term therapy. Synthetic medications are not always safe, and often cause unwanted effects^5,6,7, and non-compliance with treatment^8,9. The unsatisfactory treatment results of conventional medicine, and the side effects associated with some classes of drugs, such as steroids and theophylline, have contributed substantially to the increasing popularity of complementary and alternative medicine and, in particular, herbal medicine^10,11.

Indonesia, characterized as a tropical nation, boasts a diverse array of plants with significant potential for use as herbal medicines. Among these, ginger (Zingiber officinale) is frequently encountered¹². This particular species, known as Zingiber officinale Roscoe, is a popular spice with extensive applications. The health advantages associated with ginger are primarily linked to its phenolic compounds, including gingerols and shogaols¹³. Notably, red ginger (Zingiber officinale var. rubrum) exhibits higher levels of anti-inflammatory and antioxidant properties compared to other ginger varieties¹⁴. It ranks among the most commonly utilized medicinal plants in Indonesia. Red ginger is rich in phenolic compounds, specifically gingerol and shogaol, which demonstrate superior anti-inflammatory and antioxidant effects relative to other gingerols. While pharmacokinetic research on ginger has been documented, there remains a scarcity of studies focusing specifically on red ginger^15,16,17.

The effects of drugs are individual and can cause decreased effectiveness or even undesirable effects due to the significant genetic contribution to COPD treatment^18,19. Ginger induces bronchodilation by modulating intracellular calcium in airway smooth muscle, causing significant and rapid relaxation²⁰. The bronchodilator effect on respiratory smooth muscle is greatly influenced by the activation of Beta-2-Adrenergic (Β2A) receptors which are often associated with amino acids 16, 27, and 164^{21,22,23,24,25}.

The choice of transdermal patch route is an alternative drug delivery compared to oral and inhalation routes, because it obtains controlled, reproducible, and predictable drug release^26,27. The transdermal system acts as a drug reservoir and controls the rate of drug release^28,29,30,31. When transdermal drug flux is controlled by the system, not by the skin, then drug delivery will be more reproducible and inter-intrasubject variation is smaller because drug release from the system can be controlled accurately rather than permeability in the skin^,32,33,34,35. Other advantages of the transdermal route are non-invasiveness, compliance, and avoiding first-pass metabolism and variability of oral administration (pH-food-enzymes-transit time) can increase bioavailability and minimize side effects³⁶. Therefore, with the development of technology, this study aims to create a medical device dosage form in the form of a red ginger transdermal patch for COPD therapy. This dosage form is expected to facilitate patients in coordinating its use, increasing compliance, and efficiency in order to achieve optimal treatment results. The aim was to determine the development of a transdermal patch of red ginger (Zingiber officinale var. rubrum) for COPD treatment associated with beta-2-adrenergic receptors gene polymorphism.

The Role of Red Ginger In Copd Therapy:

Ginger has three varieties, and red ginger (Zingiber officinale var. rubrum) has greater anti-inflammatory and antioxidant content than the other 2 types¹⁴. Red ginger is one of the most widely consumed medicinal plants in Indonesia. The ginger rhizome contains phenolic compounds including gingerol and shogaol. 10-gingerol has been reported to show the greatest anti-inflammatory and antioxidant activity compared to other gingerols. Pharmacokinetic studies on ginger have been reported, but studies on red ginger are still lacking¹⁵.

Previous research by Saragih et al.¹⁶, that the soaking of red ginger ethanol extract produced in this study was 6.78%. Red ginger ethanol extract has antioxidant activity to inhibit peanut oil oxidation, this can be seen from the control peroxide value (without extract) with the addition of red ginger extract. The higher the concentration of ethanol extract, the stronger its activity in inhibiting peanut oil oxidation. The effect of red ginger on the lungs is also supported by research by Sutyarso et al.¹⁷, that ethanol extract of red ginger 200, 400 and 600mg/kgBW can reduce the number of goblet cells and increase the height of the respiratory tract cilia of white mice exposed to cigarette smoke.

In summary, both in vitro and in vivo research have demonstrated that ginger and its bioactive constituents, including 6-shogaol, 6-gingerol, and oleoresin, exhibit significant antioxidant properties. Furthermore, the activation of the Nrf2 signaling pathway plays a crucial role in the mechanism of action. It is important to note that excessive production of reactive oxygen species (ROS) in the human body is linked to the onset of various diseases. While antioxidants are theoretically expected to be beneficial, their effectiveness can be influenced by numerous factors, including health status, individual variability, lifestyle choices, other dietary components, as well as the dosage, solubility, and method of oral administration of antioxidants. These variables can impact the bioaccessibility and bioavailability of antioxidants, resulting in generally low concentrations in the bloodstream, which may account for the limited efficacy of most antioxidants in practical applications²⁰.

The Role of Beta-2-Adrenergic Receptors Gene Polymorphism In Copd Therapy:

The observed differences in individual vulnerability to negative impacts on lung function indicate a notable genetic influence on COPD¹⁸. While smoking is frequently recognized as the main cause of COPD, it is important to note that not all smokers will develop the disease, and the deterioration of lung function among smokers can differ significantly. Increasing evidence points to genetic risk factors for COPD; early studies on family aggregation and linkage analysis have provided strong indications of a genetic role in the disease, and recent genome-wide association studies have pinpointed multiple genomic regions that are distinctly linked to susceptibility to COPD and its treatment outcomes¹⁹.

Ginger induces bronchodilation by modulating intracellular calcium in airway smooth muscle, causing significant and rapid relaxation. Ginger constituents, such as gingerols and shogaols, have relaxant properties on respiratory smooth muscle in guinea pigs and human trachea. Shogaols also have the effect of inducing rapid relaxation of precontraction respiratory smooth muscle (100-300μM)²⁰.

The bronchodilator effect on respiratory smooth muscle is largely influenced by activation of Beta-2-Adrenergic (β2A) receptors. In addition to the receptors expressed on respiratory smooth muscle cells, β2A receptors are also found on a number of other cell types in the lung including epithelial cells, submucosal glands, vascular endothelium, vascular smooth muscle and inflammatory cells including mast cells, macrophages and eosinophils²¹.

In β2A, polymorphisms affecting amino acids 16, 27, and 164 are the most common and have been shown to correlate with several clinical features of asthma, including airway reactivity. The glycine-16Arg/Gly homozygous variant of β2AR is known to affect agonist-induced regulation and desensitization, and may play a role in the pathogenesis of asthma severity. Polymorphisms at position 27Gln/Glu are associated with decreased airway responsiveness. The 164Thr/Ile polymorphic variant has been shown to have impaired agonist binding and decreased adenylyl cyclase activity^22,23,24. In addition to asthma, the 16Arg/Gly gene polymorphism also shows a link to COPD²⁵.

The Role of Transdermal Patch Innovation In Copd Therapy:

On the side of the use of asthma/COPD drugs themselves, inhaler preparations are generally used because they are safer and have faster effects. This shows that the use of DPI inhalers needs to be developed because asthma patients still have difficulty using the first generation MDI type inhalers, although the use of DPIs is relatively easier but less familiar so that many patients and health workers do not understand it in detail^37,38.

A transdermal patch is an adhesive medicated patch applied to the skin, designed to administer a precise dosage of medication directly into the bloodstream. This method offers advantages over other drug delivery systems, such as oral, topical, intravenous, and intramuscular routes, by allowing for a controlled release of the medication. This controlled release is typically achieved through a porous membrane that encases the drug reservoir or by utilizing body heat to dissolve a thin layer of the drug integrated within the adhesive. However, a significant drawback of transdermal delivery systems is the skin's effectiveness as a barrier, which limits this method to drugs with sufficiently small molecules capable of penetrating the skin³⁹.

The attractiveness of utilizing the skin as a route for drug administration is attributed to its convenient accessibility, extensive surface area, and the ability to achieve systemic distribution via the underlying circulatory and lymphatic systems, along with the noninvasive characteristics of this delivery method. The main objective of a transdermal patch system is to facilitate the delivery of medications into the systemic circulation through the skin at a specified rate, while ensuring minimal variability both between different patients and within the same patient (Figure 1).

Figure 1. (a) Transdermal Batch Dosage Form⁴⁰; (b) Transdermal Patch Construction; (c) Transdermal Patch Absorption on Skin⁴⁰

Several previous studies from abroad that examined the formulation of patch dosage forms for the treatment of asthma include: tulobuterol (long-acting beta-2 agonist)⁴¹, ketotifen⁴², and theophylline⁴³.

CONCLUSION:

Red ginger has the potential to effectively transdermal patch dosage form of red ginger (Zingiber officinale var. rubrum) for COPD treatment associated with Beta-2-Adrenergic receptors gene polymorphism.

ACKNOWLEDGMENT:

This research was funded by Ministry of Education, Culture, Research and Technology, Republic of Indonesia 2024. Researchers would like to thank Institute of Research and Community Service by Universitas Surabaya.

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Received on 10.11.2024 Revised on 04.03.2025

Accepted on 14.05.2025 Published on 01.12.2025

Available online from December 06, 2025

Research J. Pharmacy and Technology. 2025;18(12):5923-5927.

DOI: 10.52711/0974-360X.2025.00856

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