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Biomaterials Nov 2023Biologics are unaffordable to a large majority of the global population because of prohibitively expensive fermentation systems, purification and the requirement for... (Review)
Review
Biologics are unaffordable to a large majority of the global population because of prohibitively expensive fermentation systems, purification and the requirement for cold chain for storage and transportation. Limitations of current production and delivery systems of biologics were evident during the recent pandemic when <2.5% of vaccines produced were available to low-income countries and ∼19 million doses were discarded in Africa due to lack of cold-chain infrastructure. Among FDA-approved biologics since 2015, >90% are delivered using invasive methods. While oral or topical drugs are highly preferred by patients because of their affordability and convenience, only two oral drugs have been approved by FDA since 2015. A newly launched oral biologic costs only ∼3% of the average cost of injectable biologics because of the simplified regulatory approval process by elimination of prohibitively expensive fermentation, purification, cold storage/transportation. In addition, the cost of developing a new biologic injectable product (∼$2.5 billion) has been dramatically reduced through oral or topical delivery. Topical delivery has the unique advantage of targeted delivery of high concentration protein drugs, without getting diluted in circulating blood. However, only very few topical drugs have been approved by the FDA. Therefore, this review highlights recent advances in oral or topical delivery of proteins at early or advanced stages of human clinical trials using chewing gums, patches or sprays, or nucleic acid drugs directly, or in combination with, nanoparticles and offers future directions.
Topics: Humans; Pharmaceutical Preparations; Administration, Topical; Proteins; Biological Products; Administration, Oral
PubMed: 37690380
DOI: 10.1016/j.biomaterials.2023.122312 -
Annals of Allergy, Asthma & Immunology... Aug 2023The current standard of first-line emergency treatment of anaphylaxis is intramuscular (IM) epinephrine, mostly administered through epinephrine autoinjector (EAI) in... (Review)
Review
PURPOSE OF REVIEW
The current standard of first-line emergency treatment of anaphylaxis is intramuscular (IM) epinephrine, mostly administered through epinephrine autoinjector (EAI) in the outpatient setting. However, undercarriage and underuse of EAIs are common, and delayed epinephrine use is associated with increased morbidity and mortality. Patients, caregivers, and healthcare professionals have expressed a strong desire for small, needle-free devices and products that would offer improved carriage, ease of use, and more convenient, less invasive routes of epinephrine administration. Novel mechanisms of epinephrine administration are under investigation to help address several recognized EAI limitations. This review explores innovative nasal and oral products under investigation for the outpatient emergency treatment of anaphylaxis.
FINDINGS
Human studies of epinephrine administered through nasal epinephrine spray, a nasal powder spray, and a sublingual film have been conducted. Data from these studies indicate promising pharmacokinetic results comparable to those of the standard of outpatient emergency care (0.3-mg EAI) and syringe and needle IM epinephrine administration. Several products have shown maximum plasma concentration values higher than those of the 0.3-mg EAI and manual IM injection, although it remains unclear whether this has clinical relevancy in patient outcomes. Generally, these modalities show comparable time to maximum concentrations. Pharmacodynamic changes observed with these products are comparable to or more robust than those seen with EAI and manual IM injection.
SUMMARY
Given comparable or superior pharmacokinetic and pharmacodynamic results and safety of innovative epinephrine therapies to those of current standards of care, US Food and Drug Administration approval of these products may help address numerous barriers that EAIs present. The ease of use and carriage and favorable safety profiles of needle-free treatments may make them an attractive alternative to patients and caregivers, potentially addressing injection fears, needle-based safety risks, and other reasons for lack of or delayed use.
Topics: Humans; Anaphylaxis; Epinephrine; Injections, Intramuscular; Emergency Medical Services; Outpatients
PubMed: 37279803
DOI: 10.1016/j.anai.2023.05.033 -
European Journal of Pharmaceutical... Nov 2023The oral delivery of biologics such as therapeutic proteins, peptides and oligonucleotides for the treatment of colon related diseases has been the focus of increasing... (Review)
Review
The oral delivery of biologics such as therapeutic proteins, peptides and oligonucleotides for the treatment of colon related diseases has been the focus of increasing attention over the last years. However, the major disadvantage of these macromolecules is their degradation propensity in liquid state which can lead to the undesirable and complete loss of function. Therefore, to increase the stability of the biologic and reduce their degradation propensity, formulation techniques such as solidification can be performed to obtain a stable solid dosage form for oral administration. Due to their fragility, stress exerted on the biologic during solidification has to be reduced with the incorporation of stabilizing excipients into the formulation. This review focuses on the state-of-the-art solidification techniques required to obtain a solid dosage form for the oral delivery of biologics to the colon and the use of suitable excipients for adequate stabilization upon solidification. The solidifying processes discussed within this review are spray drying, freeze drying, bead coating and also other techniques such as spray freeze drying, electro spraying, vacuum- and supercritical fluid drying. Further, the colon as site of absorption in both healthy and diseased state is critically reviewed and possible oral delivery systems for biologics are discussed.
Topics: Excipients; Desiccation; Freeze Drying; Biological Products; Colon
PubMed: 37429482
DOI: 10.1016/j.ejps.2023.106523 -
Clinical Oral Investigations Dec 2023The oral cavity constitutes an attractive organ for the local and systemic application of drug substances. Oromucosal tablets, gels, or sprays are examples of the... (Review)
Review
OBJECTIVES
The oral cavity constitutes an attractive organ for the local and systemic application of drug substances. Oromucosal tablets, gels, or sprays are examples of the formulations applied. Due to the elution through the saliva, the residence time of the formulation at the application site is relatively short. Medical devices placed in the oral cavity, with a reservoir for an active substance, play an important role in solving this problem.
MATERIALS AND METHODS
In this review, we discuss the devices described in the literature that are designed to be used in the oral cavity, highlighting the advantages, disadvantages, and clinical applications of each of them.
RESULTS
Among the intraoral medical devices, special types are personalized 3D-printed devices, iontophoretic devices, and microneedle patches.
CONCLUSION
We anticipate that with the development of 3D printing and new polymers, the technology of flexible and comfortable devices for prolonged drug delivery in the oral cavity will develop intensively.
CLINICAL RELEVANCE
The presented review is therefore a useful summary of the current technological state, when in fact none of the existing devices has been widely accepted clinically.
Topics: Drug Delivery Systems; Printing, Three-Dimensional; Tablets
PubMed: 37982874
DOI: 10.1007/s00784-023-05377-5 -
BMC Psychiatry Aug 2023Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission.
METHODS
Post hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined.
RESULTS
The median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up.
CONCLUSION
Treatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality.
TRIAL REGISTRATION
ClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).
Topics: Adult; Humans; Depressive Disorder, Major; Antidepressive Agents; Suicidal Ideation; Suicide; Double-Blind Method; Treatment Outcome
PubMed: 37568081
DOI: 10.1186/s12888-023-05017-y -
Shanghai Kou Qiang Yi Xue = Shanghai... Aug 2023Monkeypox is becoming a viral infectious disease of global concern. WHO has reported monkeypox outbreaks in more than 50 countries. Since the first imported case has... (Review)
Review
Monkeypox is becoming a viral infectious disease of global concern. WHO has reported monkeypox outbreaks in more than 50 countries. Since the first imported case has been confirmed and reported by Taiwan, China, in June 2022, the monkeypox has draw high attention from the national public health and epidemic prevention department. Among the key tasks of Shanghai high-quality healthcare development in 2023, monkeypox has been identified as one of the key infectious diseases that need to be under strict prevention and control. The diagnosis and treatment in dental department are mainly performed face-to-face, with patients' masks taken-off. Large amount of aerosol spray will be generated during the operation. At the same time, dental diagnosis and treatment is in outpatient department, where the patient flow is large. Once monkeypox patients have been diagnosed and treated in the dental diagnosis and treatment area, and the preventive measures are not implemented, it will provide convenience for monkeypox to transmit. In order to avoid this kind of situation, this article made a review of monkey-pox from the following 3 aspects: epidemic transmission history of monkeypox, systemic and oral symptoms of monkeypox, and oral prevention of monkeypox, to improve the knowledge and prevention ability of dental medical staff on monkeypox for early recognition and prevention.
Topics: Humans; Mpox (monkeypox); China; Public Health; Outpatients; Quality of Health Care
PubMed: 38044724
DOI: No ID Found -
Food Safety (Tokyo, Japan) Sep 2023Food Safety Commission of Japan (FSCJ) conducted a risk assessment of cyphenothrin (CAS No. 39515-40-7), a pyrethroid insecticide, intended to be used to exterminate...
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of cyphenothrin (CAS No. 39515-40-7), a pyrethroid insecticide, intended to be used to exterminate cockroaches in piggeries. This was based on documents of pigsty sprays containing the active substance ∙-T-Cyphenothrin submitted, and risk assessment reports of EPA (Environmental Protection Agency) and others. The data of -T80-Cyphenothrin and -T-Cyphenothrin, with different abundance ratios of the eight optical isomers composing both cyphenothrins, were used for the evaluation. The data used in the assessment include pharmacokinetics (rats), residues (rats), genotoxicity, acute toxicity (mice and rats), subacute toxicity (mice, rats and dogs), chronic toxicity/carcinogenicity (mice, rats and dogs), reproductive toxicity (rats and rabbits), neurotoxicity (rats), general pharmacology and others. In the various genotoxicity tests, no genotoxicity of -T80-Cyphenothrin were observed on living organisms. -T-Cyphenothrin was not expected to cause genotoxity from the results of -T80-Cyphenothrin studies. FSCJ thus recognized it to be possible to specify an acceptable daily intake (ADI). The lowest no-observed-adverse-effect level (NOAEL) obtained from all the studies was 3 mg/kg bw per day. This value was based on the following effects of administration using -T80-Cyphenothrin in dogs: Vomiting in a 13-week subacute toxicity study in males and females, and vomiting and redness of the oral mucous membranes in a 52-week chronic toxicity study in males. Addition of the safety factor 2 was appropriate based on the fact that the toxicity of -T-Cyphenothrin was slightly stronger than that of -T80-Cyphenothrin. FSCJ thus specified an acceptable daily intake (ADI) of 0.015 mg/kg bw per day after applying a safety factor of 200 to the NOAEL.
PubMed: 37745162
DOI: 10.14252/foodsafetyfscj.D-23-00008 -
Diabetes, Obesity & Metabolism Aug 2023Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity...
AIMS
Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear.
MATERIALS AND METHODS
We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions).
RESULTS
We found significant negative associations between age and insulin action in the hippocampus (β = -0.215; p = .017) and caudate nucleus (β = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions.
CONCLUSION
We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Insulin; Insulin Resistance; Brain; Insulin, Regular, Human; Glucose Tolerance Test
PubMed: 37046367
DOI: 10.1111/dom.15094 -
Pharmaceutics Dec 2023Developing drugs that are highly selective to host tissues but are the least toxic remains one of the most difficult challenges in cancer treatment. Recent studies have...
Developing drugs that are highly selective to host tissues but are the least toxic remains one of the most difficult challenges in cancer treatment. Recent studies have shown that tumor cells from a variety of sources can express vitamin D3 receptors and that the response to vitamin D3 and its analogs is prone to growth arrest and cell death. However, conventional vitamin D3 drug formulations lack dose control and cannot target specific cells or tissues. The aim of this study was to prepare vitamin D3 nanospray for inhalation delivery route. This study evaluated the physical properties of the formulation (particle size distribution and biological stability), the total number of sprays per bottle, the spray volume per spray, and the loading variance of the spray. The optimized vitamin D3 spray formula is easy to spray, has fewer drips, and has a fast drying time. It can be stored for 3 months at 37 ± 2 °C temperature, 75 ± 5% relative humidity, and away from light, and can maintain biological stability. This study showed that compared with traditional nasal sprays, the spray has a larger fan angle (82.1 degrees) and beam width (104.88 mm), more symmetrical spray on both sides of the spray column, a faster coverage of the administration site, and a wider range, which is suitable for inhalation delivery routes.
PubMed: 38258036
DOI: 10.3390/pharmaceutics16010025 -
Life (Basel, Switzerland) Nov 2023Chronic rhinosinusitis (CRS) is an important ENT pathology which affects about 5-12% of the general population. The treatment of CRS can be pharmacological (nasal... (Review)
Review
Chronic rhinosinusitis (CRS) is an important ENT pathology which affects about 5-12% of the general population. The treatment of CRS can be pharmacological (nasal sprays, douches, systemic antibiotics and steroids), surgical (endoscopic sinus surgery) or immunological according to established algorithms. CRS was divided for many years into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). New ways of classifying CRS by endotypes (presence of neutrophilia, eosinophilia, fibrosis, glandular hypertrophy and epithelial dysmorphisms) appeared after the most recent understandings of the pathophysiology of the disease. Other classifications divide CRS into primary and secondary forms, localized/diffuse types and anatomical presentation. A new type of treatment has been administered in the last years, biologics. For the moment, biologics are indicated just in the cases of the patients who have undergone ESS or have contraindications for surgery and have bilateral polyps and meet a minimum of three of the following criteria: the necessity for systemic therapies with oral or parenteral corticosteroids or contraindications to systemic steroids, significant loss of smell or impaired QoL score, comorbid asthma and type 2 inflammation. This article aims to present the most relevant studies which used the three types of biologics (anti-IgE, anti-IL5 and anti-IL4/IL3) and wishes to increase the awareness of this new type of treatment that can be used in some CRS cases.
PubMed: 38004305
DOI: 10.3390/life13112165