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Formulation Discussion
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US FDA approves ViiV Healthcare’s Dovato for HIV-infected patients who have never received treatment for HIV
Drug Discovery, Formulation Discussion

The US Food and Drug Administration (FDA) approved ViiV Healthcare’s Dovato (dolutegravir and lamivudine), as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no antiretroviral treatment history and with no known or suspected substitutions associated with resistance to the individual components of Dovato. This is the first FDA-approved two-drug, fixed-dose, complete regimen for HIV-infected adults who have never received treatment for HIV.

“Currently, the standard of care for patients who have never been treated is a three-drug regimen. With this approval, patients who have never been treated have the option of taking a two-drug regimen in a single tablet while eliminating additional toxicity and potential drug interactions from a third drug,” said Debra Birnkrant, M.D., Director of the Division of Antiviral Products. “Having a drug-sparing treatment available that uses fewer drugs is beneficial to patients who may have issues taking multiple medications over a long period of time.”

Approximately 1.1 million people in the US are living with HIV. About 15 percent of them (1 in 7) are unaware they are infected. Effective treatment is important in reducing the amount of virus in the blood. A suppressed viral load in people living with HIV prevents disease progression, and helps them live longer, healthier lives. Also, people living with HIV who take HIV medication daily as prescribed and maintain an undetectable viral load have effectively no risk of sexually transmitting HIV to their HIV-negative partners.

The Dovato labeling includes a Boxed Warning, which cautions that patients infected with both HIV and hepatitis B should add additional treatment for their hepatitis B or consider a different drug regimen. Patients with both HIV and hepatitis B who take products containing lamivudine, an ingredient in Dovato, have developed hepatitis B variants associated with resistance to lamivudine and may have severe liver problems, including liver failure, when they stop taking drugs containing lamivudine. Patients who have both HIV and hepatitis B virus who stop using Dovato should be closely monitored by their health care provider.

The efficacy and safety of Dovato, one tablet taken daily, were demonstrated in two identical, randomized, double-blind, controlled clinical trials in 1,433 HIV-infected adults with no prior antiretroviral treatment history. The trials showed that a drug regimen containing dolutegravir and lamivudine had a similar effect of reducing the amount of HIV in the blood compared to another drug regimen, which included dolutegravir, emtricitabine, and tenofovir. The treatment was considered successful if the patient maintained low-levels (less than 50 copies/mL) of HIV RNA in their blood for at least 48 weeks.

The most common adverse reactions with Dovato were headache, diarrhea, nausea, insomnia and fatigue. As there is a known risk for neural tube defects with dolutegravir, patients are advised to avoid use of Dovato at the time of conception through the first trimester of pregnancy. In May 2018, the FDA released a Drug Safety Communication regarding reported neural tube birth defects in babies born to women treated with dolutegravir.

In Feb. 2019, the US Department of Health and Humans Services announced a new initiative, Ending the HIV Epidemic: A Plan for America, a once-in-a-generation opportunity to eliminate new HIV infections in our nation. This initiative will provide the hardest hit communities with the additional expertise, technology and resources required to address the HIV epidemic in their communities, focusing on certain geographic hotspots. The aim is to reduce new infections by 75 percent in the next five years and by 90 percent in the next ten years, averting more than 250,000 HIV infections in that span.


Mylan introduces generic Brevibloc in US markets
Drug Discovery, Formulation Discussion, Pharma News
Hertfordshire, England
Saturday, September 15, 2018, 12:00 Hrs  [IST]

Global pharmaceutical company Mylan N.V. announced the US launch of esmolol hydrochloride in sodium chloride injection, 2,500 mg/250 mL (10 mg/mL) single-dose plastic bag and 2,000 mg/100 mL (20 mg/mL) single-dose plastic bag, the first generic version of the reference listed drug, Baxter’s Brevibloc.

Mylan is offering esmolol hydrochloride in sodium chloride injection, 2,500 mg/250 mL (10 mg/mL) single-dose plastic bag and 2,000 mg/100 mL (20 mg/mL) single-dose plastic bag to its institutional customers after an Abbreviated New Drug Application (ANDA) for the product was approved by the US Food and Drug Administration (FDA). Esmolol hydrochloride in sodium chloride injection is indicated for the short-term treatment of control of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia and control of perioperative tachycardia and hypertension.

US sales for sodium chloride injection, 2,500 mg/250 mL (10 mg/mL) single-dose plastic bag and 2,000 mg/100 mL (20 mg/mL) single-dose plastic bag were approximately US$ 126 million for the 12 months ending June 30, 2018, according to IQVIA.

Currently, Mylan has 189 ANDAs pending FDA approval representing approximately US$ 91.5 billion in annual brand sales, according to IQVIA. Forty-three of these pending ANDAs are potential first-to-file opportunities, representing US$ 50.6 billion in annual brand sales, for the 12 months ending June 30, 2018, according to IQVIA.

Courtesy – Pharnabiz

‘Extraordinary growth’ on the cards for cancer immunotherapies !
Drug Discovery, Formulation Discussion, Pharma News

Domainex invests in NanoTemper MST technology to advance fragment-based drug discovery services
Drug Discovery, Formulation Discussion, Pharma News

Sandeep Singh Dhillon
How Pacira Pharma Is Working To Help Curb The Opioid Epidemic – Pharmaceutical Online Newsletter
Formulation Discussion, Pharma Extra
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Poorly managed postoperative pain can have a significant impact on a patient’s recovery. For example, it can put them at risk for medical complications, including deep vein thrombosis, pulmonary embolus, and pneumonia.1 In addition, today’s methods for drug delivery often introduce a drug into the body in large quantities where it must then systematically travel until it reaches the intended area. This wide-scale distribution increases the potential for harmful side effects and requires a higher cost for care due to the amount of drug needed.

Another concern about the impact of poorly managed postoperative pain is related to the use of opioids for pain relief and a rise in the misuse and abuse of these drugs by patients. In a recent study from Stanford University, researchers found that patients undergoing 11 of the most common types of surgery were at increased risk for chronic opioid use.2 The increased use of opioids after surgery has caused a cascade into the abuse of prescription painkillers, and opioid dependence rose more than 3,000 percent from 2007 to 2014.3 According to AddictionCenter.com, there are an estimated 4.7 million people in the United States dependent on painkillers.4

To address this epidemic, the FDA assembled a task force in 2013, which, among other efforts, encouraged the development of abuse-deterrent formulations of opioids. However, the most effective way to stop opioid dependence is to eliminate the use of these highly addictive drugs after surgery altogether. This was the goal of Pacira Pharmaceuticals, Inc., a specialty pharmaceutical company focused on the development of non-opioid products for postsurgical pain control, when it developed its injectable suspension, EXPAREL® (bupivacain liposome injectable suspension).

Changing The Standard Of Care

EXPAREL is a local analgesic utilizing bupivacaine in combination with the product delivery platform DepoFoam®. DepoFoam is made of microscopic polyhedral particles composed of numerous nonconcentric internal chambers that encapsulate a drug. These discrete chambers are separated by lipid membranes and filled with an aqueous solution of a drug. Once the drug is inside the DepoFoam technology and injected into the patient, the body begins to break down the lipid membranes. This is a naturally occurring process that releases the drug without altering its molecular structure.

DepoFoam permits both systemic and local delivery, which means the platform can release drugs into the bloodstream via the interstitial space or into a body compartment, such as a joint. This targeted delivery system allows the injection of drugs into the areas of the body where pain receptors exist, focusing the administration of EXPAREL to only the areas where it is needed.

The delivery of the non-opioid drug, EXPAREL, through the DepoFoam technology provides physicians and patients with the tools necessary to overcome the challenges associated with managing postoperative pain. “EXPAREL limits the amount of [opioid] drug needed after surgery, and, as a result, the potential for adverse effects is reduced dramatically,” says Ray Kaczmarek, Vice President of Commercial Manufacturing and Supply Operations at Pacira. “Most importantly, it empowers physicians to change the standard of care for postsurgical pain and ultimately gets the patient back up on their feet without the severe adverse events or the side effects of an opioid.” After it is infiltrated into the surgical wound prior to closure, EXPAREL can deliver up to 72 hours of postsurgical analgesia, Kaczmarek says. This significantly reduces pain during the first 24 to 48 hours after surgery, when it is often the most severe.

Addressing The Challenges Of EXPAREL Manufacturing

Beyond the composition of lipid components and the need for aqueous excipients, the effectiveness of the DepoFoam delivery platform is dependent on the manufacturing process used to develop it. Kaczmarek says one challenge is the critical need to properly handle EXPAREL in its sterile state. “Once we start the process of creating the liposome, we have to maintain sterility assurance all the way through to the patient,” he explains. “That means the bulking process, the filling process, and everything done until the point where the physician begins to utilize the drug.” Other important factors for the successful manufacturing of EXPAREL include temperature, agitation, and the design of the sterility assurance package around the drug.

What also makes the manufacturing process for EXPAREL challenging is the need for a manufacturer to understand the complexity of the drug’s critical process parameters and how they interrelate to each one of its attributes. If any one of the parameters is changed, the drug product will either fall apart or will not work in an appropriate way. Additionally, the limitations of today’s downstream technologies create a manufacturing bottleneck that makes the scale up of EXPAREL difficult. “The sooner the industry starts improving downstream technologies, the sooner we will be able to maximize the technologies, such as TFF [tangential flow filtration], to improve our manufacturing scale,” explains Kaczmarek. “Until then, we’re creating newer platforms and utilizing different technologies to allow the maximization of scaling by limiting exposure in the downstream process and implementing continuous batch processing.”

It was these challenges, as well as the need for global exposure and regulatory compliance, that caused Pacira to seek a partner who could provide them with the resources and experience necessary to build upon their existing manufacturing capacity to successfully manufacture and globally commercialize EXPAREL. After vetting other prospects, Pacira decided on Patheon. Kaczmarek says what was particularly appealing about Patheon is that the relationship between the two companies is not a typical CDMO/sponsor relationship. “I’m not just handing the drug product over and then hoping they manufacture and provide the supply to me,” he explains. “We’re working together to transfer a complex manufacturing process into one of their suites, and then, within that work, expanding the process out and training their personnel on how to run it. We will monitor the process as a partner as they manufacture the drug product.” This is accomplished through the use of Patheon’s condominium manufacturing model. The “condo” model is one of six adaptable manufacturing arrangements the CDMO offers its clients. Through multiple options, Patheon provides sponsors with a variety of flexible and scalable manufacturing approaches to create the optimal solution to fit a client’s needs.

A Stronger Partnership Through Collaboration And Communication

Patheon’s condo model is designed for companies either expanding their current manufacturing capacity or introducing new product with unique characteristics that cannot be manufactured on a conventional manufacturing line, such as EXPAREL. In addition to providing manufacturing design services, Patheon works with equipment suppliers, validates the processes, builds the line, and manages operations on behalf of the client. Overhead is shared, and the line can operate as needed to meet demand.

Kaczmarek says Pacira personnel support the manufacturing and quality assurance processes in Patheon’s UK facility. “This gives us the ability to utilize the facility, the staffing, and the support structure Patheon brings to the table,” he says. “They also have multiple areas outside of the U.K. facility where we can continue to grow strategically.” Kaczmarek adds that Pacira wanted a manufacturing agreement and strategic partner, not just a one-time partner for one product. They potentially want to utilize Patheon for their pipeline. “We want to take the new technologies we are developing and place them into Patheon’s facilities, so they can be co-located with the people who are learning the processes and understanding our drug. Patheon provides the ability for us to do that through the condo model and the footprint design they have in their U.K. facility.”

The condo model design coupled with the manufacturing agreement gave Pacira a high level of confidence that they not only picked the right partner, but they would also be able to control the intellectual property of their drug product design and formulation. “Other potential manufacturing groups we were looking at did not have the same type of model, nor did they have the same ability to provide that type of an operational environment where we could transfer a very complex process to them with the understanding of how they would actually be able to manufacture moving forward,” says Kaczmarek.

As the next step toward creating an even stronger relationship, Pacira and Patheon are establishing a governance relationship, where both companies speak on a regular basis about topics like how the U.K. facility is being utilized and whether the product is being fully commercialized in an appropriate way. “Patheon’s openness to the integration of these types of technologies into their network maximizes Pacira’s ability to supply EXPAREL to patients, as well as our future pipeline,” says Kaczmarek. “By having these strategic discussions and agreements, it minimizes the cost of manufacturing for both companies and it maximizes the ability to provide patients the quality drug products in a very timely manner. Ultimately, that’s what we want to be able to do, and both companies are coming together to make that possible.”

Sandeep Singh Dhillon
What Your Pharmacist Can’t Tell You About Drug Expiration Dates: ‘It’s Complicated’ – Medical Daily
Formulation Discussion, Pharma Notables

One of the most common questions people ask health care providers is, Can I use my old drugs past their expiration dates?

The short, safe answer is a simple “no.” However the truth of the matter is much more intricate, a lot more interesting, and requires a bit of knowledge about the Food and Drug Administration (FDA).

In the late 1970s, the FDA first began requiring expiration dates on both prescription and over-the-counter medications.

“To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing,” reads the agency’s regulation. The FDA permits “reasonable variation,” meaning manufacturers are given a little leeway, so long as the any medication marketed in the United States contain between 90 percent to 110 percent of the amount of the active ingredient claimed on the label.

“Just having the slight variation of 90 to 110 percent, well, it would be very difficult, from a manufacturing standpoint, to hone it down even more than that,” Dr. Lee Cantrell, of the California Poison Control System and UC San Francisco School of Pharmacy, told Medical Daily.

The legal code adopted by the FDA also notes that manufacturers must account for storage conditions (and reconstitution conditions for certain drugs) in the expiration date. As a result of FDA rules, then, you will find a date, usually following the letters ‘EXP,’ either printed on the label or stamped onto the bottle or carton of drugs you buy, and in other cases, crimped into the tube of certain ointments you purchase.

The expiration date of most medicines is 12 to 60 months after manufacture, reports Pharmacy Times. According to Pittsburgh-Post Gazette, pharmacists further shorten the time a medicine can be used when they add their own “discard after” or “beyond-use” date to the prescription label itself. From manufacturer to FDA to pharmacist, the underlying principle is maximum safety.

Seems like the end of the story, at least from the FDA’s perspective. However, if you are looking for an intelligent rebuttal of expiration dates, the best place to turn is to the very same alphabet soup government agency, the FDA.


In the mid-1980s, as described by an article appearing in Biosecurity and Bioterrorism, the Air Force approached the FDA about “the possibility of safely extending the expiration dates of some of the drugs that it had stockpiled.” The Department of Defense routinely stockpiles medications for future use by both the military and civilians. This expensive process includes costs for planning, proper storage, and also reeplacing expired drugs. Since the latter cost eats up a significant portion of the Air Force budget, the Shelf Life Extension Program (SLEP) was proposed and undertaken by the FDA in 1985 to determine the actual shelf life of stockpiled drugs. In short, SLEP was born to save taxpayer dollars.

In its inaugural 1985 run, the program tested 56 drugs and found it was possible to extend the shelflife of 80 percent of them (and 84 percent of the tested lots) by as much as three years. With lots of dollars saved, the program naturally didn’t end there. An update of SLEP in 2006 investigated stability profiles for 122 different drug products (slightly more than 3,000 different lots) and resulted in a lifespan extension of at least one year beyond the original expiration date for 88 percent of the lots. The average additional time added to each drug was 66 months.

Among the drugs tested and approved for continued use were two antibiotics, amoxicillin (commonly prescribed to children) and ciprofloxacin (commonly called ‘cipro’ and used to treat anthrax infections), an antihistamine (diphenhydramine, often used to treat allergies), and a morphine sulfate injection (a painkiller).

Certainly, the FDA has provided comprehensive information suggesting required expiration dates may not be as firm as most consumers suppose, and this is substantiated by the work of others. In 2009, The Medical Letter, an independent nonprofit that provides unbiased drug-prescribing recommendations to professionals, reviewed the most recent data on the same subject. Importantly, the publication addresses safety first.

The authors found just one report of a patient who may have been harmed by taking an expired drug. This singular case, involving a patient who may have suffered kidney damage after taking expired tetracycline (an antibiotic), occurred more than 40 years ago. (Since that era, tetracycline products have been reformulated.)

Noting storage in heat and high humidity may shorten a drug’s half-life, The Medical Letter report also acknowledges that in many published studies a variety of medications stored under “stress” conditions remained chemically and physically stable for up to nine years beyond their expiration dates. Generally, the authors warn, liquid drugs are not as stable as solid dosages, and should a liquid become cloudy, discolored, or show signs of precipitation, it should not be used.

“Many drugs stored under reasonable conditions in their original unopened containers retain 90 percent of their potency for at least 5 years after the expiration date on the label, and sometimes much longer,” The Medical Letter report concludes, with one important caveat: “Epinephrine in EpiPen is an important exception” as these products gradually lose potency once the expiration date passes.

Cantrell and his colleagues travel an inspired path to scientific gold, arriving at a similar conclusion for their 2012 study.

In his wanderings, Cantrell “stumbled across” a box of drugs, all of which had expired 28 to 40 years prior. Unearthed in a family-owned pharmacy generations old, the box contained drugs which had remained in their original, unopened containers for decades. In “the name of science,” Cantrell and friends undertook analysis of the drugs.

In the lab, tablets were dissolved, isotopes diluted, chromatography tests run. Three times, the science crew tested and retested samples for listed active ingredients. What did they discover?

Of the 14 drugs, 12 (or 86 percent) were present in concentrations at least 90 percent of the labeled amounts, which is the generally recognized minimum acceptable potency. Surprisingly, three of these compounds were present at greater than 110 percent of the labeled content. The team found two compounds (aspirin and amphetamine) in amounts of less than 90 percent; meanwhile, another ingredient (phenacetin) appeared at greater than 90 percent in one drug but less than 90 percent in another.

“Given the potential cost-savings, we suggest the current practices of drug expiration dating be reconsidered,” Cantrell and his co-authors wrote in the conclusion.

Speaking with Medical Daily, Cantrell advised caution.

“My study didn’t convey anything about safety, I just looked at potency of active ingredients,” he said. Though an active ingredient may be as strong as the manufacturer originally intended, this does not mean the overall drug — a chemical jamboree, essentially — remains non-toxic, he explained. In fact, no scientific study has ever tested expired medications in human subjects and so he does not advocate using drugs past their due dates.

“I myself wouldn’t feel comfortable taking an outdated antibiotic, if you’re trying to kill a potentially life-threatening bug invading my system,” he said.

The Future of Pharmacy Jobs — Will It Be Feast or Famine? – A Medscape review
Drug Discovery, Formulation Discussion, Pharma News

Sandeep Singh Dhillon
What you need to know about immediate, delayed and extended-release medications – MIMS Malaysia
Formulation Discussion, Pharma Notables
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Recognising correct drug formulation is an important aspect of medical treatment. There are distinct pharmacokinetic differences between oral formulations such as immediate-release, extended-release and delayed-release although the drug composition and strength are identical. Unfortunately, these distinctions may not be apparent to many doctors or pharmacists, and the specific terms may be incorrectly used interchangeably. In addition, new formulations of the same pharmaceutical ingredients frequently enter the market, thus creating more confusion.

Henceforth, it is pivotal for both doctors and pharmacists to understand the fundamental differences between various formulation types to ensure optimum treatment. For pharmacists, failure to recognize and dispense the correct formulation may constitute negligence which can directly cause harm to patients.
Immediate-release formulation

The most commonly seen formulation in Malaysia is the immediate-release medication. These standard drug products are designed to release the active pharmaceutical compound immediately after the outer shell of tablets/capsule dissolves. There is no deliberate attempt to modify the release profile. For highly soluble drugs, this may result in rapid absorption and fast systemic entry into the body, i.e. a prompt increase in blood concentration of that particular drug. The accompanying clinical effect will be seen as soon as the plasma concentration reaches the therapeutic level (1).

There are exceptions to the above-mentioned observation. Some medicines are formulated as pro-drugs, which mean the pharmaceutical compound itself does not have therapeutic effects until it undergoes hepatic metabolism and transformed into the active compound. In this case, the pharmacodynamic effect may not be apparent until there is enough conversion of the pro-drugs into their active form. Alternatively, many drugs which are poorly soluble (i.e. lipophilic) may not be rapidly absorbed, thus delaying its clinical effect (1).
Modified-release formulation

On the other hand, modified-release formulations are specially designed to alter the drug release profile, thereby favourably affecting the absorption time and subsequent pharmacodynamic effects. The term “modified release” is rather all-encompassing, including many different types of formulations currently available in the market such as extended-release and delayed-release formulation.
Extended-release formulation

Extended-release formulation allows at least twofold reduction in dosage frequency as compared to the immediate-release ones, as described in Applied Biopharmaceutics & Pharmacokinetics (1). Several technologies have been successfully employed to control drug release profiles, such as microencapsulation and diffusion systems.
Know the differences

When compared to delayed-release dosage forms, there are many similarities amidst some distinct differences. A delayed-release product is a formulation that only releases the medication until the tablet has passed through the stomach, as explained by Fava and Holquist (2).

To illustrate the differences between extended- and delayed-release, one can refer to the case of Depakote (divalproex sodium) formulations. Depakote received attention from the medical community, especially the US FDA when the agency received a couple of medication errors pertaining to a mix-up of extended- and delayed-release formulation. Depatoke is indicated for the treatment of manic episode in patients with bipolar disorder whom lithium is contraindicated or not tolerated (3).

Existing pharmacokinetic data indicated that there were significant differences between the plasma concentration profile for both dosage forms. The bioavailability of extended-release Depakote was 10% less than an equivalent dose of delayed-release formulation (2).

It is vital for pharmacists to be aware of such differences for many other drugs. These different dosage forms commonly appear to be comparable to each other in terms of visual similarities and sound-alike names. Vigilance is a valuable trait when prescribing or dispensing such medications. MIMS

1. Shargel L, Wu-Pong S, Yu A. Chapter 17. Modified-Release Drug Products. Applied Biopharmaceutics & Pharmacokinetics. 6th Editio. New York: McGraw-Hill Medical; 2012.
2. Fava W, Holquist C. FDA safety page: Delayed-release vs. extended-release Rxs [Internet]. Drug Topics – Voice of the pharmacist. 2007 [cited 2016 Jul 20]. Available from: http://drugtopics.modernmedicine.com/drug-topics/news/clinical/pharmacy/fda-safety-page-delayed-release-vs-extended-release-rxs?page=full
3. Sanofi. Depakote 250mg Tablets [Internet]. eMedicine Compendium. 2009 [cited 2016 Jul 20]. Available from: https://www.medicines.org.uk/emc/medicine/25929

Drug makers kept many clinical trial results a secret: study
Drug Discovery, Formulation Discussion

Is the R&D tax break really an incentive to innovate?
Drug Discovery, Formulation Discussion, Regulatory Affairs