透皮贴剂经皮递送PBPK模型建模方法概述

doi:10.12092/j.issn.1009-2501.2026.02.010

摘要/Abstract

摘要：

透皮贴剂作为应用广泛但开发复杂的仿制药剂型，其临床生物等效性试验开展难度较高，针对此，监管机构鼓励采用生理药代动力学（physiologically based pharmacokinetic，PBPK）模型引导研发，以降低成本并提升成功率。透皮贴剂的PBPK建模关键影响因素包括药物特性、制剂系统与机体差异。药物因素方面，定量结构-性质关系（quantitative structure-property relationship，QSPR）模型基于相对分子质量、脂水分配系数（LogP）等参数预测分配与扩散系数；机制模型通过解析多层皮肤结构阐明渗透动力学过程。制剂系统中，骨架型与储库型贴剂的释放差异可通过多相多层皮肤吸收机制（multiphase multilayered mechanistic dermal absorption，MPML MechDermA）模型模拟，涵盖溶出、沉淀及载体蒸发等关键过程。机体差异上，皮肤厚度、pH值、附属器密度及病理状态等显著影响渗透效率，模型需结合年龄、性别、种族等变量校准。模型整合基于菲克定律构建隔室间药物转运方程，支持体外-体内外推（in vitro to in vivo extrapolation，IVIVE）。本文系统综述透皮贴剂开发的PBPK建模方法及其影响因素，有望减少动物实验并加速临床转化。

关键词: 透皮贴剂, 生理药代动力学, 药物因素, 制剂因素, 生理因素

Abstract:

As a widely used generic dosage form with complex development, transdermal patches pose high challenges in conducting clinical bioequivalence studies. In response, regulatory authorities encourage the adoption of physiologically based pharmacokinetic (PBPK) model-guided development to reduce costs and improve success rates. The key influencing factors for PBPK modeling of transdermal patches include drug properties, formulation systems, and inter-individual variations. Regarding drug factors, quantitative structure-property relationship (QSPR) models predict partition and diffusion coefficients based on parameters like molecular weight and lipophilicity (LogP). Mechanistic models elucidate permeation kinetics by resolving the multilayered skin structure. For formulation systems, release differences between matrix-type and reservoir-type patches can be simulated using the multiphase multilayered mechanistic dermal absorption (MPML MechDermA) model, covering key processes like dissolution, precipitation, and vehicle evaporation. Concerning inter-individual variability, factors like skin thickness, pH, appendage density, and pathological states significantly impact permeation efficiency. Models require calibration using variables such as age, gender, and race. The model integrates drug transport equations between compartments based on Fick's law, supporting in vitro-in vivo extrapolation (IVIVE). This article systematically reviews the PBPK modeling methods and their influencing factors in the development of transdermal patches, promising to reduce animal experiments and accelerate clinical translation.

Key words: transdermal patches, physiologically based pharmacokinetic, drug factors, formulation factors, physiological factors

中图分类号:

戚大可, 车津晶. 透皮贴剂经皮递送PBPK模型建模方法概述[J]. 中国临床药理学与治疗学, 2026, 31(2): 223-239.

Dake QI, Jinjing CHE. Overview of PBPK modeling method for transdermal patch delivery[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(2): 223-239.

图/表 5

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105	Jin FQ, Knight AE, Cardones AR, et al. Semi-automated weak annotation for deep neural network skin thickness measurement[J]. Ultrason Imaging, 2021, 43 (4): 167- 174. doi: 10.1177/01617346211014138
106	Zhong F, Lu H, Meng R, et al. Effect of penetration enhancer on the structure of stratum corneum: On-site study by confocal polarized Raman imaging[J]. Mol Pharmaceutics, 2024, 21 (3): 1300- 1308. doi: 10.1021/acs.molpharmaceut.3c00978
107	Shigeno A, Miyao D, Futagami H, et al. Phenol burns treated with conservative therapy: a case report[J]. Burns Open, 2024, 8 (2): 115- 119. doi: 10.1016/j.burnso.2024.02.005
108	Cheruvu HS, Liu X, Grice JE, et al. Modeling percutaneous absorption for successful drug discovery and development[J]. Expert Opin Drug Discov, 2020, 15 (10): 1181- 1198. doi: 10.1080/17460441.2020.1781085

Parameter	Formula	Remark	Reference
Partition Coefficient
K_SC:w	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 5.4({K}_{\text{ow}}{)}^{0.27}\\&+{f}_{\text{lip}}\times 0.43({K}_{\text{ow}}{)}^{0.81}+{f}_{\mathrm{w}}\end{aligned} $	Value of ρ_pro, ρ_lip and ρ_w are 1.37 g/cm³, 0.9 g/cm³ and 1 g/cm³.The volume fractions of protein, lipid and water phase are denoted as f_pro, f_lip and f_w respectively, f_pro = 0.1476, f_lip = 0.0671, f_w = 0.7853. K_ow is the octanol-water partition coefficients.	[10-11]
	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 5.6({K}_{\text{ow}}{)}^{0.27}\\&+{f}_{\text{lip}}\times 0.35({K}_{\text{ow}}{)}^{0.81}+{f}_{\mathrm{w}}\end{aligned} $		[10]
	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 4.23({K}_{\text{ow}}{)}^{0.31}\\&+{f}_{\text{lip}}\times \dfrac{{\rho }_{\text{lip}}}{{\rho }_{\mathrm{w}}}\times ({K}_{\text{ow}}{)}^{0.69}+{f}_{\mathrm{w}}\end{aligned} $		[11]
	$ {K}_{\text{SC}\colon \mathrm{w}}=0.014{\left({K}_{\text{ow}}\right)}^{0.81}+\dfrac{0.782}{f\,{}_{non}^{SC}}+1.381{\left({K}_{\text{ow}}\right)}^{0.27} $	Fully hydrated SC At the pH value designated for SC, the parameter $ f\,{}_{non}^{SC} $ represents the nonionized fraction of unbound weak electrolytes within the interiors of corneocytes.	[12]
	$ {K}_{\text{SC}\colon \mathrm{w}}=0.040{\left({K}_{\text{ow}}\right)}^{0.81}+\dfrac{0.359}{f\,{}_{non}^{SC}}+4.057{\left({K}_{\text{ow}}\right)}^{0.27} $	Partially hydrated SC	[12]
K_VE:w	$ {K}_{VE\colon w}={K}_{D\colon w}=0.7\times \left(0.68+\dfrac{0.32}{{f}_{u}}+0.025\times {f}_{non}\times K_{ow}^{0.7}\right) $	The fraction of solute that is non-ionized in the aqueous phase is denoted as f_non, while f_u represents the fraction of solute that is unbound (to albumin).	[13]
Diffusion coefficient
D_SC (cm²/h)	$ {D}_{SC}=\dfrac{5.6\times {10}^{-6}\mathrm{K}_{\text{ow}}^{0.7}{\mathrm{e}}^{-0.46{{\mathrm{r}}^{2}}}\times {h}_{\text{SC}}}{{K}_{SC\colon w}} $	r is the radius of the solute molecule.h_SC is the SC thickness, h_SC =14 μm	[9, 14]
D_VE (cm²/h)	$ {D}_{VE}={D}_{D}=\dfrac{{10}^{-8.15-0.655\times \log MW}}{0.68+\tfrac{0.32}{{f}_{u}}+0.025\times {f}_{non}\times \tfrac{{\rho }_{\text{lip}}}{{\rho }_{\mathrm{w}}}\mathrm{K}_{\text{ow}}^{0.69}} $		[9, 15]
D_sb (cm²/h)	$ {D}_{sb}=2.48\times {10}^{-4}{e}^{-0.42\times {{r}^{2}}} $		[16]

Parameter	Formula	Remark	Reference
Partition Coefficient
K_SC:w	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 5.4({K}_{\text{ow}}{)}^{0.27}\\&+{f}_{\text{lip}}\times 0.43({K}_{\text{ow}}{)}^{0.81}+{f}_{\mathrm{w}}\end{aligned} $	Value of ρ_pro, ρ_lip and ρ_w are 1.37 g/cm³, 0.9 g/cm³ and 1 g/cm³.The volume fractions of protein, lipid and water phase are denoted as f_pro, f_lip and f_w respectively, f_pro = 0.1476, f_lip = 0.0671, f_w = 0.7853. K_ow is the octanol-water partition coefficients.	[10-11]
	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 5.6({K}_{\text{ow}}{)}^{0.27}\\&+{f}_{\text{lip}}\times 0.35({K}_{\text{ow}}{)}^{0.81}+{f}_{\mathrm{w}}\end{aligned} $		[10]
	$ \begin{aligned} {K}_{\text{SC}\colon \mathrm{w}}&={f}_{\text{pro}}\times \dfrac{{\rho }_{\text{pro}}}{{\rho }_{\mathrm{w}}}\times 4.23({K}_{\text{ow}}{)}^{0.31}\\&+{f}_{\text{lip}}\times \dfrac{{\rho }_{\text{lip}}}{{\rho }_{\mathrm{w}}}\times ({K}_{\text{ow}}{)}^{0.69}+{f}_{\mathrm{w}}\end{aligned} $		[11]
	$ {K}_{\text{SC}\colon \mathrm{w}}=0.014{\left({K}_{\text{ow}}\right)}^{0.81}+\dfrac{0.782}{f\,{}_{non}^{SC}}+1.381{\left({K}_{\text{ow}}\right)}^{0.27} $	Fully hydrated SC At the pH value designated for SC, the parameter $ f\,{}_{non}^{SC} $ represents the nonionized fraction of unbound weak electrolytes within the interiors of corneocytes.	[12]
	$ {K}_{\text{SC}\colon \mathrm{w}}=0.040{\left({K}_{\text{ow}}\right)}^{0.81}+\dfrac{0.359}{f\,{}_{non}^{SC}}+4.057{\left({K}_{\text{ow}}\right)}^{0.27} $	Partially hydrated SC	[12]
K_VE:w	$ {K}_{VE\colon w}={K}_{D\colon w}=0.7\times \left(0.68+\dfrac{0.32}{{f}_{u}}+0.025\times {f}_{non}\times K_{ow}^{0.7}\right) $	The fraction of solute that is non-ionized in the aqueous phase is denoted as f_non, while f_u represents the fraction of solute that is unbound (to albumin).	[13]
Diffusion coefficient
D_SC (cm²/h)	$ {D}_{SC}=\dfrac{5.6\times {10}^{-6}\mathrm{K}_{\text{ow}}^{0.7}{\mathrm{e}}^{-0.46{{\mathrm{r}}^{2}}}\times {h}_{\text{SC}}}{{K}_{SC\colon w}} $	r is the radius of the solute molecule.h_SC is the SC thickness, h_SC =14 μm	[9, 14]
D_VE (cm²/h)	$ {D}_{VE}={D}_{D}=\dfrac{{10}^{-8.15-0.655\times \log MW}}{0.68+\tfrac{0.32}{{f}_{u}}+0.025\times {f}_{non}\times \tfrac{{\rho }_{\text{lip}}}{{\rho }_{\mathrm{w}}}\mathrm{K}_{\text{ow}}^{0.69}} $		[9, 15]
D_sb (cm²/h)	$ {D}_{sb}=2.48\times {10}^{-4}{e}^{-0.42\times {{r}^{2}}} $		[16]

Influencing Factors	Skin Parameters
	pH	TEWL	Skin Thickness	Skin Lipids	Skin Moisture	Melanin	Sweat Glands	Hair Follicles	Keratinocytes	Skin Microbiota	Skin Metabolism	Skin Blood Flow
Age
Newborns	The skin pH of newborns within 15 days after birth is significantly higher than that of adults, approximately 6.0. It then gradually decreases, stabilizing at around 5.1 at 2 months, and remains approximately the same at 4 - 5 years old^[70].	Compared with adults, the TEWL of newborns is significantly lower on the forehead, palms, and soles, higher on the forearm, and has no difference on the abdomen and back^[71].	Thinner than adults / no difference^[53]	Lower content than adults^[53]	Higher content than adults^[53]	Lower content than adults^[72]	Lower sweating volume than adults^[73]	-	-	-	-	-
Children	-	-	Thinner than adults before 6 years old ^[53]	Denser than adults before 6 years old^[53]	-	Less than adults, increasing with age^[53]	-	-	Smaller than adults before 6 years old^[53]	Predominated by Firmicutes on the forearm^[53]	-	-
Elderly	Slightly increased on the volar forearm, temple, forehead, back, and neck; the pH reaches its maximum value in the 50 - 60 - year - old age group, and the skin pH of the elderly over 70 years old decreases comprehensively^{[64, 74]}	-	Becomes thinner after 65 years old^[75]	Content decreases after 65 years old^[75]	Content decreases after 65 years old^[75]	-	-	-	-	-	Decreases after 65 years old^[75]	Decreases / remains unchanged after 65 years old^[75]
Gender	In areas such as the forehead, inner forearm, outer forearm, and face, the pH value of men is lower than that of women. The average pH value on the surface of men's forehead is 4.5, while that of women is 5^[7].	-	-	-	-	-	-	The distribution and number of men are usually more than those of women, but the impact on the barrier function may have little difference^[76]	-	-	May be different between men and women^[77]	-
Race	-	Higher in black people than in white people. Black people have a high spontaneous desquamation rate and a high incidence of clinical xerosis^[78-79]	Thinner epidermis in Asians^[56]	-	Higher content in Asians than in Caucasians^[80]	Faster skin aging in Caucasians^[54]	More in Asians^[56]	-	-	Higher density of Propionibacterium on the skin of African - Americans^[81]	-	-
Special Populations
Pregnant Women	-	-	Decreases^[82]	-	Content increases^[82]	-	-	-	-	-	-	Increases^[82]
Obese	-	-	-	-	-	-	-	-	-	-	Altered^[59]	Accelerated^[59]
Skin Injuries
Mechanical Injury	-	Increases^[69]	-	-	-	-	-	-	-	-	-	-
Frostbite	-	Unchanged^[69]	-	-	-	-	-	Lipid bilayer structure altered^[69]	-	-	-	-
Burn	-	The water evaporation from the exposed burn wound is approximately 1/3 higher than that of normal skin^[83]	-	-	-	-	-	-	-	-	-	-
Inflammatory Skin Diseases	-	Increases, desquamation rate increases^[84]	-	-	-	-	-	-	-	-	-	-
Essential Fatty Acid Deficiency	-	-	-	-	-	-	-	Epidermal hyperplasia with acanthosis and hyperkeratosis^[85]	-	-	-	-
Psoriasis	-	Increases^[64]	-	-	-	-	-	-	-	-	--	-
Atopic Dermatitis	-	Increases^[86]	-	-	-	-	-	-	-	-	-	-
Exfoliative Dermatitis	-	Increases^[87]	-	-	-	-	-	-	-	-	-	-
Eczema	-	-	-	-	-	-	-	-	Altered^[88]	-	-
Fungal Infections	-	-	-	-	-	-	-	Parakeratosis, intercellular / intracellular edema^[89]	-	-	-	Vasodilation^[89]
Keratosis Diseases (Ichthyosis)	-	-	-	-	-	-	-	-	Related to disease classification, different classifications have different permeabilities^[90]	-	-	-
Basal Cell Carcinoma	-	-	-	-	-	-	-	-	-	-	-	Blood perfusion in the basal cell carcinoma area is 2.5 times higher than that in the healthy area^[91]
Administration Sites
Scalp	-	-	Thicker^[7]	-	-	-	Abundant^[7]	Abundant^[7]	-	-	-	-
Face	-	-	Thinner^[92]	-	-	-	-	-	-	-	-	Abundant^[7]
Trunk	-	-	Uneven^[7]	-	-	-	-	-	-	-	-	Abundant^[7]
Arm	-	-	Medium^[93]	-	-	-	Medium ^[93]	Medium ^[93]	-	-	-	Medium ^[93]
Thigh	-	-	Thicker^[7]	-	-	-	Abundant^[7]	Abundant^[7]	-	-	-	Abundant^[7]
Forehead	-	-	Thinner^[93]	-	-	-	-	-	-	-	-	-

Influencing Factors	Skin Parameters
	pH	TEWL	Skin Thickness	Skin Lipids	Skin Moisture	Melanin	Sweat Glands	Hair Follicles	Keratinocytes	Skin Microbiota	Skin Metabolism	Skin Blood Flow
Age
Newborns	The skin pH of newborns within 15 days after birth is significantly higher than that of adults, approximately 6.0. It then gradually decreases, stabilizing at around 5.1 at 2 months, and remains approximately the same at 4 - 5 years old^[70].	Compared with adults, the TEWL of newborns is significantly lower on the forehead, palms, and soles, higher on the forearm, and has no difference on the abdomen and back^[71].	Thinner than adults / no difference^[53]	Lower content than adults^[53]	Higher content than adults^[53]	Lower content than adults^[72]	Lower sweating volume than adults^[73]	-	-	-	-	-
Children	-	-	Thinner than adults before 6 years old ^[53]	Denser than adults before 6 years old^[53]	-	Less than adults, increasing with age^[53]	-	-	Smaller than adults before 6 years old^[53]	Predominated by Firmicutes on the forearm^[53]	-	-
Elderly	Slightly increased on the volar forearm, temple, forehead, back, and neck; the pH reaches its maximum value in the 50 - 60 - year - old age group, and the skin pH of the elderly over 70 years old decreases comprehensively^{[64, 74]}	-	Becomes thinner after 65 years old^[75]	Content decreases after 65 years old^[75]	Content decreases after 65 years old^[75]	-	-	-	-	-	Decreases after 65 years old^[75]	Decreases / remains unchanged after 65 years old^[75]
Gender	In areas such as the forehead, inner forearm, outer forearm, and face, the pH value of men is lower than that of women. The average pH value on the surface of men's forehead is 4.5, while that of women is 5^[7].	-	-	-	-	-	-	The distribution and number of men are usually more than those of women, but the impact on the barrier function may have little difference^[76]	-	-	May be different between men and women^[77]	-
Race	-	Higher in black people than in white people. Black people have a high spontaneous desquamation rate and a high incidence of clinical xerosis^[78-79]	Thinner epidermis in Asians^[56]	-	Higher content in Asians than in Caucasians^[80]	Faster skin aging in Caucasians^[54]	More in Asians^[56]	-	-	Higher density of Propionibacterium on the skin of African - Americans^[81]	-	-
Special Populations
Pregnant Women	-	-	Decreases^[82]	-	Content increases^[82]	-	-	-	-	-	-	Increases^[82]
Obese	-	-	-	-	-	-	-	-	-	-	Altered^[59]	Accelerated^[59]
Skin Injuries
Mechanical Injury	-	Increases^[69]	-	-	-	-	-	-	-	-	-	-
Frostbite	-	Unchanged^[69]	-	-	-	-	-	Lipid bilayer structure altered^[69]	-	-	-	-
Burn	-	The water evaporation from the exposed burn wound is approximately 1/3 higher than that of normal skin^[83]	-	-	-	-	-	-	-	-	-	-
Inflammatory Skin Diseases	-	Increases, desquamation rate increases^[84]	-	-	-	-	-	-	-	-	-	-
Essential Fatty Acid Deficiency	-	-	-	-	-	-	-	Epidermal hyperplasia with acanthosis and hyperkeratosis^[85]	-	-	-	-
Psoriasis	-	Increases^[64]	-	-	-	-	-	-	-	-	--	-
Atopic Dermatitis	-	Increases^[86]	-	-	-	-	-	-	-	-	-	-
Exfoliative Dermatitis	-	Increases^[87]	-	-	-	-	-	-	-	-	-	-
Eczema	-	-	-	-	-	-	-	-	Altered^[88]	-	-
Fungal Infections	-	-	-	-	-	-	-	Parakeratosis, intercellular / intracellular edema^[89]	-	-	-	Vasodilation^[89]
Keratosis Diseases (Ichthyosis)	-	-	-	-	-	-	-	-	Related to disease classification, different classifications have different permeabilities^[90]	-	-	-
Basal Cell Carcinoma	-	-	-	-	-	-	-	-	-	-	-	Blood perfusion in the basal cell carcinoma area is 2.5 times higher than that in the healthy area^[91]
Administration Sites
Scalp	-	-	Thicker^[7]	-	-	-	Abundant^[7]	Abundant^[7]	-	-	-	-
Face	-	-	Thinner^[92]	-	-	-	-	-	-	-	-	Abundant^[7]
Trunk	-	-	Uneven^[7]	-	-	-	-	-	-	-	-	Abundant^[7]
Arm	-	-	Medium^[93]	-	-	-	Medium ^[93]	Medium ^[93]	-	-	-	Medium ^[93]
Thigh	-	-	Thicker^[7]	-	-	-	Abundant^[7]	Abundant^[7]	-	-	-	Abundant^[7]
Forehead	-	-	Thinner^[93]	-	-	-	-	-	-	-	-	-

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