The influence of the gut microbiota on the bioavailability of oral drugs

Due to its safety,convenience,low cost and good compliance,oral administration attracts lots of attention.However,the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract.One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs,influencing the drug transport process and altering some gastrointestinal properties.In this review,we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs,which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nanocarriers(NCs:silica nanospheres and gold nanocages)with poly-l-lysine(PLL)coating and mammalian orthoreovirus cell attachment proteinσ1 functionalization(NC-PLL-σ1)were explored as functional oral drug delivery vehicles(ODDVs).The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells(M-cells)mediated transcytosis(viaσ1-α2–3-linked sialic acids adherence)across gastrointestinal epithelia.PLL coating provided protection and slow-release of rhodamine 6 G(R6G),a model payload.The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro.When compared with other experimental groups,the fully functionalized ODDV system(with PLL-σ1)demonstrated two significant advantages:a significantly higher transport efficiency(198%over blank control at 48 h);and protection of payloads which led to both better transport efficiency and extended-release of payloads(61%over uncoated carriers at 48 h).In addition,it was shown that the M cell presence in intestinal organoid monolayers(modulated by Rank L stimulation)was a determining factor on the transport efficiency of the ODDVs:more M-cells(induced by higher Rank L)in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload(R6G).The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition)

Oral drugs such as ibrutinib play an important role in the treatment of mature B-cell lymphoma(BCL)due to their reliable efficacy,manageable safety,high accessibility,and convenience for use.Still,no guidelines or consensus focusing on oral drug therapies for BCL is available.To provide a reference of oral agent-based treatment for mature BCL,a panel of experts from the Lymphocyte Disease Group,Chinese Society of Hematology,Chinese Medical Association conducted an extensive discussion and reached a consensus on oral drugs for Chinese BCL patients on the basis of the current application status of oral drugs in China,combined with the latest authoritative guidelines in the world and current research reports.This consensus reviewed the application of oral drugs in the treatment of BCL and the latest research and provided appropriate recommendations on the use of oral drugs for indolent or aggressive BCL patients.With the deepening of research and the development of standardized clinical applications,oral medications will bring better treatment to BCL patients,enabling more patients to benefit from them.

UNIQUE ORAL DRUG DELIVERY SYSTEM

An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid spheres at stomach pH's (1--3). These spheres also dissemble atintestinal pH's (6--7) releasing the drug for absorption. Using this technique low molecularweight heparin and human growth hormone have been orally delivered successfully to severalanimal species. Future work has been proposed to study the interaction and binding of thespecific drugs with synthesized oligopeptides.

Biphasic insulin aspart 30 improved glycemic control in Chinese patients with type 2 diabetes poorly controlled on oral glucose-lowering drugs： a subgroup analysis of the A1chieve study

Background The effectiveness and safety of initiating biphasic insulin aspart 30 in patients who were poorly controlled on oral glucose-lowering drugs were studied in randomized controlled trials,while results from clinical practice remain limited.This subgroup analysis was to provide such findings from a large-scale non-interventional study.Methods A1chieve was a multinational,prospective,open-label,non-interventional,24-week study in patients with type 2 diabetes initiating insulin analogues in 28 countries across Asia,Africa,Europe,and Latin America.After physician had taken the decision to use this insulin,any patient with type 2 diabetes who was not treated with or who had started the study insulin within 4 weeks before inclusion was eligible.Patients were treated with study insulin alone or in combination with oral glucose-lowering drugs.Data on adverse drug reactions,hypoglycemia and glycemic control were collected at baseline,week 12 and 24.This is a report of a Chinese subgroup analysis from the A1chieve study.Results Totally,4 100 patients constituted this subgroup.No serious adverse drug reactions were reported.Rates of total,major,nocturnal hypoglycemic events （events/patient per year） were 1.47,0.10,0.31 at baseline and 1.35,0.00,0.22 at week 24,respectively.Glycemic control was improved as measured by hemoglobin A1c （mean 9.3％ to 7.0％,reduction -2.3％）,fasting plasma glucose （mean 10.2 to 6.8 mmol/L,reduction-3.5 mmol/L） and postprandial plasma glucose （mean 14.4 to 8.8 mmol/L,reduction-5.6 mmol/L）,all P ＜0.001.Change in mean body weight was ＋0.3 kg （P ＜0.001）.Conclusion In this subgroup analysis of the A1chieve study,biphasic insulin aspart 30 improved glycemic control with low risk of hypoglycemia.

Treatment of type 2 diabetes mellitus in the elderly

The prevalence of type 2 diabetes is expected to increase gradually with the prolongation of population aging and life expectancy. In addition to macrovascular and microvascular complications of elderly patients of diabetes mellitus, geriatric syndromes such as cognitive impairment, depression, urinary incontinence,falling and polypharmacy are also accompanied by aging. Individual functional status in the elderly shows heterogeneity so that in these patients, there are many unanswered questions about the management of diabetes treatment. The goals of diabetes treatment in elderly patients include hyperglycemia and risk factors, as in younger patients. comorbid diseases and functional limitations of individuals should be taken into consideration when setting treatment targets. Thus, treatment should be individualized. In the treatment of diabetes in vulnerable elderly patients, hypoglycemia, hypotension, and drug interactions due to multiple drug use should be avoided. Since it also affects the ability to self-care in these patients, management of other concurrent medical conditions is also important.

Recent advances in new-onset diabetes mellitus after kidney transplantation

A common challenge in managing kidney transplant recipients(KTR)is posttransplant diabetes mellitus(PTDM)or diabetes mellitus(DM)newly diagnosed after transplantation,in addition to known pre-existing DM.PTDM is an important risk factor for post-transplant cardiovascular(CV)disease,which adversely affects patient survival and quality of life.CV disease in KTR may manifest as ischemic heart disease,heart failure,and/or left ventricular hypertrophy.Available therapies for PTDM include most agents currently used to treat type 2 diabetes.More recently,the use of sodium glucose co-transporter 2 inhibitors(SGLT2i),glucagon-like peptide-1 receptor agonists(GLP-1 RA),and dipeptidyl peptidase 4 inhibitors(DPP4i)has cautiously extended to KTR with PTDM,even though KTR are typically excluded from large general population clinical trials.Initial evidence from observational studies seems to indicate that SGLT2i,GLP-1 RA,and DPP4i may be safe and effective for glycemic control in KTR,but their benefit in reducing CV events in this otherwise high-risk population remains unproven.These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status,pre-existing burden of peripheral vascular disease,urinary tract infections due to immunosuppression and a surgically altered urinary tract,erythrocytosis from calcineurin inhibitors,and reduced kidney function from acute or chronic rejection.

Influence of solvent mixtures on HPMCAS-celecoxib microparticles prepared by electrospraying

Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.

Determinants for inadequate glycaemic control in Chinese patients with mild-to-moderate type 2 diabetes on oral antidiabetic drugs alone

Background Prevalence of inadequate glycaemic control among patients with type 2 diabetes mellitus （T2DM） remains high. We assessed glycaemic control in the real-life practice among people with T2DM in metropolises in China who were treated with oral antidiabetic drugs （OAD） alone and to determine factors associated with inadequate glycaemic control in this population. Methods An observational, cross-sectional multicentre study was conducted in 16 metropolitan medical centers. People with T2DM who had been followed-up before the index visit which occurred from January to September 2007 were included in the study. All subjects were 〉30 years of age at the time of T2DM diagnosis and had received monotherapy or combination therapy of OAD for at least 6 months. Demographic and clinical data were collected from medical records. The main study outcome was the inadequate glucose control rate, which was calculated by the proportion of patients with haemoglobin Alc （HbAlc） 〉6.5% detected on the index visit. Results In this cohort of 455 patients with T2DM whose mean age was 60.6 years and mean disease duration was 6.1 years, 45.5% had inadequate glycaemic control. The mean （SD） HbA1c was 6.7% （1.3）. Multivariate Logistic regression showed that physical inactivity, disease duration 〉10 years, body mass index （BMI） ≥24 kg/m2, low homeostasis model assessment of β-cell function （HOMA-13） index, less frequency of medical visit and hypertriglyceridaemia were independent determinants of inadequate glycaemic control. Higher incidence of self-reported hypoglycemia experience （47.1% vs. 34.8%, P=0.008） and more fear of hypoglycemia quantified by Worry subscale of the Hypoglycaemia Fear Survey （HFS） II were happened in subjects with good glycemic control. Conclusion Approximately one half of these outpatients with T2DM from the metropolitan medical centers in China had inadequate glycaemic control treated with OAD alone, which raises the need for more effective educational and therapeutic approaches on management of hypertriglycemia, enhancing physical exercise and weight control, and at the same time. Iowerina the hvooalvcemic risk and diminishina the hvooalvcemic fear of oatients.

Pharmacotherapy of Diabetes Mellitus Type 2: A Review on Various Hypoglycemics

Diabetes is a cosmopolitan medical issue ramifying a large population regardless of ethnicity.Elevated glycemic condition in a patient is explained as diabetes.It can be mainly categorized into Non-Insulin Dependent Diabetes Mellitus(NIDDM)and Insulin Dependent Diabetes Mellitus(IDDM)or Type 1 or Type 2 respectively.Type 1 or IDDM needs insulin therapy exclusively while Type 2 can be controlled via various hypoglycemic agents.Conventional classes contain glitazones,biguanides,sulfonylurea’s and soon,while newly developed drug classes include gliptins or DPP-4 inhibitors,SGLT-2 receptor inhibitors and GLP-1 receptor agonists.The novelty in the anti-hyperglycemic agents have given promising results as compared to the conventional drugs.Insulin cannot be negated as far as its glycemic control is concerned.Furthermore,development of Insulin analogues like detemir,glargine,Lisprohave been shown to control glucose levels in the plasma more efficiently.

Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer

Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the present work,gastrodin,the main bioactive ingredient of the traditional Chinese drug“Tianma”(Rhizoma Gastrodiae)was used as a model drug to explore reasonable application of borneol.Sustained-release solid dispersions(SRSDs)for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder.The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy,differential scanning calorimetry,and powder X-ray diffractometry.The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form.Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model.Subsequently,gastric mucosa irritation and the brain targeting of the SRSDs were evaluated.Compared with the free mixture of gastrodin and borneol,brain targeting of SRSDs was slightly weaker(brain targeting index:1.83 vs.2.09),but stomach irritation obviously reduced.Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.

Milk-derived exosomes exhibit versatile effects for improved oral drug delivery

As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.

A “cluster bomb” oral drug delivery system to sequentially overcome the multiple absorption barriers

Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cluster bomb” oral drug delivery system (DOX@PFeL@L100) with core-shell structure to overcome the complex absorption barriers. The inner core termed as “bomb” that contains a lot of ultra-small diameter Fe_(3)O_(4) nanoparticles (DOX@PFeL NPs) loaded with doxorubicin (DOX) and modified with l-valine, which can efficiently penetrate the epithelial cells via PePT1 receptor mediated endocytosis. The outer shell of this “cluster bomb” is a layer of pH-sensitive polymer (Eudragit®L100) that can be served as a pH-responsive switch and effectively control the “bomb” release in the intestinal microenvironment to improve the antitumor efficiency by the Fenton like reaction of DOX and Fe^(2+)/Fe^(3+). This study demonstrates that the “cluster comb” oral drug delivery system can sequentially overcome the multiple biological barriers, providing a safe and effective approach for tumor therapy.

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration(oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent bile acid transporter-mediated intestinal uptake and lymphatic transportation.In this system,taurocholic acid(TCA)modified poly(lactic-co-glycolic acid)(PLGA)was employed to achieve pancreas location,hydroxychloroquine(HCQ)was loaded to execute therapeutic efficacy,and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC)was introduced as stabilizer together with synergist(PLGA-TCA/DLPC/HCQ).In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction,thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day.In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress,remodeled the inflammatory pancreas microenvironment,and activated PI3K/AKT signaling pathway without obvious toxicity.This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

Membrane fusion reverse micelle platforms as potential oral nanocarriers for efficient internalization of free hydrophilic peptides

Orally administered peptides or proteins are garnering increasing preference owing to their superiority in terms of patient compliance and convenience.However,the development of oral protein formulations has stalled due to the low bioavailability of macromolecules that encounter the aggressive gastrointestinal environment and harsh mucus villi barrier.Herein,we propose an ideal reverse micelle/self-emulsifying drug delivery system(RM/SEDDS)nanoplatform that is capable of improving the oral bioavailability of hydrophilic peptides by preventing enzymatic degradation and enhancing mucosal permeability.Upon the passage through the mucus,the self-emulsifying drug delivery system with optimal surface properties effectively penetrates the viscoelastic mucosal barrier,followed by the exposure of the inner reverse micelle amphipathic vectors,which autonomously form continua with the lipidic cell membrane and facilitate the internalization of drugs.This membrane-fusion mechanism inaugurates a new way for hydrophilic peptide delivery in the free form,circumventing the traditional impediments of the cellular internalization of nanocarriers and subsequent poor release of drugs.And more importantly,reverse micelles are not spatially specific to the laden drugs,which enables their delivery for a myriad of peptide clinical drugs.In conclusion,as an exquisitely designed nanoplatform,RM/SEDDS overcomes multiple physiological barriers and opens a new path for drug cellular entry,providing new prospects for the development of oral drug delivery systems.

Advancements in oral therapeutic drugs for treating SARS-CoV-2 infections:A comprehensive review

SARS-CoV-2 has undergone five major transformations from its original strain,evolving through Alpha,Beta,Gamma,Delta,and now Omicron.The Omicron variant stands out for its high transmissibility,reduced severity,mild symptoms,and low mortality.Today,Omicron infections have become akin to common upper respiratory tract infections,underscoring the critical role of oral therapeutic drugs in clinical settings.These small-molecule oral antivirals are game-changers,effectively preventing mild and moderate cases from escalating to severe conditions and significantly reducing mortality among severe cases.They have emerged as the frontline defenders in the fight against SARS-CoV-2.Currently,eight oral antiviral drugs have been approved for use,including four 3CL protease inhibitors(nirmatrelvir/ritonavir,simnotrelvir/ritonavir,atilotrelvir/ritonavir,ensitrelvir,and leritrelvir),and three RNA polymerase inhibitors(molnupiravir,azvudine,and deuterium remdesivir).These medications are readily available and have ensured an uninterrupted clinical supply.With the establishment of a robust post-infection immune barrier and the widespread clinical use of oral antiviral drugs,the global threat posed by the COVID-19 pandemic has significantly diminished.The relentless march of scientific progress and medical innovation has turned the tide,making COVID-19 a manageable part of our lives.

Factors related to compliance with oral analgesic treatment of inpatients with chronic pain

This study aimed to determine the relationship between the different factors of analgesic therapy and the compliance of chronic pain inpatients. We prospectively investigated 100 consecutive inpatients with non- cancer chronic pain who were hospitalized to receive oral analgesic treatment in the Pain Department of West China Hospital from May 2013 to October 2013. Patients who completed the treatment plan were recorded as good compliance, whereas patients who partly completed or even refused the treatment were recorded as moderate or non-compliance, respectively. A total of 73 （73.7%）, 17 （17.1%）, and 9 （9.2%） patients showed good, moderate, and non-compliance, respectively. Univariate analyses showed significantly better compliance among farmers, patients educated in college or above, with family income of 〈 3000 CNY, and with severe or moderate pain than those employed and unemployed （P= 0.02）, patients educated below college （P= 0.013）, with family income of ≥ 3000 CNY （P = 0.025）, and with mild pain （P 〈 0.001）, respectively. Logistic regression analysis showed that the family income of≥ 3000 CNY （OR： 2.50, 95%CI： 1.65-4.51, P= 0.021） and mild pain （OR： 1.27, 95%CI： 1.03-3.31, P= 0.016） were associated with moderate or non-compliance with oral analgesic treatment. In conclusion, the low compliance with oral treatment of analgesics was found in Chinese inpatients with chronic pain and compliance was negatively associated with family income and degree of pain of patients.

Oral delivery of polyester nanoparticles for brain-targeting: Challenges and opportunities

Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance;and(4) restriction by the BBB. Then the key factors influencing brain-targeting efficiency of orally administered polyester nanoparticles are also discussed, such as size, shape and surface properties. Finally, recent brain-targeting delivery strategies using oral polyester nanoparticles as carriers and their effects on brain drugs transport are reviewed, and the delivery ‘as a whole’ strategy of polyester nanoparticles will provide new insight for oral brain-targeting delivery. And by combination of multiple strategies, both the stability and permeability of polyester nanoparticles can be greatly improved for oral brain drug delivery.

Enhanced oral drug delivery by mimicking natural amino acid and oligopeptide absorption route

Oral delivery of protein and peptide drugs presents considerable challenges due to their susceptibility to digestive enzymes in gastrointestinal(Gl)tract and low efficiency of transepithelial transport.Herein,inspired by efficient absorption of protein-based nutrients,we constructed several kinds of oral drug delivery systems by mimicking natural amino acid and oligopeptide absorption route.Three kinds of amino acids and two kinds of oligopeptides were chosen as targeting ligands to mediate transportation of orally administered nanoparticles(NPs).Liraglutide(Lira),a kind of glucagon like peptide-1(GLP-1)receptor agonist,was used as model drug.These functionalized NPs could protect Lira from enzymatic degradation in Gl tract.Moreover,compared with amino acid-modified NPs,oligopeptide-modified NPs exhibited greater transepithelial transport efficiency and were primarily absorbed in the proximal small intestine due to the high expression and transportation mediated by proton coupled oligopeptide transporter 1(PEPT1).These Lira-loaded NPs could effectively control the blood glucose level,reduce plasma lipid level,and repair tissue damage on type 2 diabetic mice and even showed comparable hypoglycemic effects of subcutaneous injection(s.c.)free Lira.Our study demonstrates the potential of mimicking natural oligopeptide absorption route to enhance oral delivery of protein and peptide drugs.